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Payments Accepted Year Established Languages Spoken Reviews I lost 20 lbs in 4 weeks!, 1/15/2009 I was a bit sceptical because there were a couple of negative comments, but decided to go with the majority and I could never be more right. Xtreme Boot Camp helped me lose 20 pounds in 1 month! I... have been working out, dieting (I thought)and running for the last TWO years with almost no results. Ashley is amazing!!! I finally feel like my hard work is paying off. #1, 9/07/2008 OK, I never left a review so this is the 1st for me. I had to write this after reading the last post. I did the xtreme boot camp in late spring and could have not immagine it would be better. Not... only did we all love Pete and how he cared and pushed us to achive, but I actually loved what I was doing. The excercise, the food, the homework. I lost exactly what I wanted and felt great. You must follow the directions to the letter to be able to do that though. I also did one month of personal training and lost as much as during the boot camp. Love the trainers, everyday's a different routine, never dull. Keep up the great work Pete and your staff. Will see you really soon. Reviews This is dad0378's TrustRating, which is based on both the number of reviews dad0378 has written, and how many other people have voted those reviews as "helpful." It's a way to quickly to determine the value of any single review or reviewer, because it's based on how helpful dad0378 has been to the Kudzu community. I lost 20 lbs in 4 weeks! Share: I was a bit sceptical because there were a couple of negative comments, but decided to go with the majority and I could never be more right. Xtreme Boot Camp helped me lose 20 pounds in 1 month! I have been working out, dieting (I thought)and running for the last TWO years with almost no results. Ashley is amazing!!! I finally feel like my hard work is paying off. This is lenila's TrustRating, which is based on both the number of reviews lenila has written, and how many other people have voted those reviews as "helpful." It's a way to quickly to determine the value of any single review or reviewer, because it's based on how helpful lenila has been to the Kudzu community. #1 Share: OK, I never left a review so this is the 1st for me. I had to write this after reading the last post. I did the xtreme boot camp in late spring and could have not immagine it would be better. Not only did we all love Pete and how he cared and pushed us to achive, but I actually loved what I was doing. The excercise, the food, the homework. I lost exactly what I wanted and felt great. You must follow the directions to the letter to be able to do that though. I also did one month of personal training and lost as much as during the boot camp. Love the trainers, everyday's a different routine, never dull. Keep up the great work Pete and your staff. Will see you really soon. This is fitnessbuff's TrustRating, which is based on both the number of reviews fitnessbuff has written, and how many other people have voted those reviews as "helpful." It's a way to quickly to determine the value of any single review or reviewer, because it's based on how helpful fitnessbuff has been to the Kudzu community. Absolutely HORRIBLE! Share: I thought the least I could do was warn those in the area. My wife enrolled in the XTbootcamp in Suwanee, GA. It was horrible and despite ALL the clams she so NO results and the instructor whom i believe was the owner knew about as much about nutrition and exercise as she did. I would NEVER pay for their services and if can save one person by writing this it was worth my time!!!! please do not trust your health to these idiots! Xtreme Transformations replied on 07-21-2008 Wow! First of all, being the owner of the company this is the first time I am hearing this and I am completely shocked! We welcome all comments, positive and negative with good reason. I am very surprised that I didn't hear anything like this when we personally call each participant half way through the camp to get their comments and answer any questions. In addition, upon completion of the camp, each participant receives a survey regarding their experience that they can answer anonymously. I personally read all of the surveys and I have never heard anything like this. Please read the other reviews we have received and look at our before and after pictures. You will then see that the program delivers exactly what it promises to. Regarding the nutrition aspect, I have a bachelors degree in health promotion, as well as hold a nutrition certification. We hire only reputable and qualified trainers and instructors which are some of the best in the industy. We have received such honorable awards as "Best of Gwinnett" from Gwinnett Magazine, readers choice award from "Accent Gwinnett Magazine" and have been featured on international networks such as CNN. This is Kentibur's TrustRating, which is based on both the number of reviews Kentibur has written, and how many other people have voted those reviews as "helpful." It's a way to quickly to determine the value of any single review or reviewer, because it's based on how helpful Kentibur has been to the Kudzu community. Thanks! Share: My husband and I have been working out with Olga and Alyte over the past two months. During our first month both of us lost lots of pounds and inches! The staff is so friendly and you can tell they really want you to suceed. We have a long way to our goal, but with the Xtreme Transformations team, we know we will get there! This is Ridgerunner's TrustRating, which is based on both the number of reviews Ridgerunner has written, and how many other people have voted those reviews as "helpful." It's a way to quickly to determine the value of any single review or reviewer, because it's based on how helpful Ridgerunner has been to the Kudzu community. Unique Workout Space Share: My wife and I consider Pete and his small cadre of trainers an extension of family. The environment is friendly, encouraging, safe, and professional. They understood our unique needs and abilities, didn't try to have us "fit" into one size fits all system. and have helped us to nt just feel healthy again, but to improve our physical AND mental health. Their new location near Suwanee Town Center provides the perfect work out environment for my wife and me. I'm 55 and feel 40 (or younger) again. Thanks Pete and crew! This is chinonyle's TrustRating, which is based on both the number of reviews chinonyle has written, and how many other people have voted those reviews as "helpful." It's a way to quickly to determine the value of any single review or reviewer, because it's based on how helpful chinonyle has been to the Kudzu community. This is not a GYM! Share: I was terrified of gyms before I called Xtreme Transformations. Here I am 6 months later and I have never felt better. The weight is melting off and my clothes fit so much better, I can;t wait to see the end result. This is mjs1322's TrustRating, which is based on both the number of reviews mjs1322 has written, and how many other people have voted those reviews as "helpful." It's a way to quickly to determine the value of any single review or reviewer, because it's based on how helpful mjs1322 has been to the Kudzu community. Alyte is great !!! Share: I have had over 6 trainers in the past ten years and without a doubt, Alyte is the best trainer I've ever had. Her workouts firm and tone (and better yet,lift) without causing me to bulk up. I gain muscle easily and this is the first time I have seen results like this. She has a great personality and is fun to be around even when she is pushing you to do something you might not really feel like doing at the time. :) I highly recommend her. This is TammyA's TrustRating, which is based on both the number of reviews TammyA has written, and how many other people have voted those reviews as "helpful." It's a way to quickly to determine the value of any single review or reviewer, because it's based on how helpful TammyA has been to the Kudzu community. This is AwesomelyBlessed's TrustRating, which is based on both the number of reviews AwesomelyBlessed has written, and how many other people have voted those reviews as "helpful." It's a way to quickly to determine the value of any single review or reviewer, because it's based on how helpful AwesomelyBlessed has been to the Kudzu community. Xtreme-ly Awesome Share: I have struggled with being overweight for a very long time, but thanks to Kim and her wonderful Bootcamp & creating my personal nutrition plans, I now have the confidence, courage and know-how to live healthy and stay fit. This is meldrob's TrustRating, which is based on both the number of reviews meldrob has written, and how many other people have voted those reviews as "helpful." It's a way to quickly to determine the value of any single review or reviewer, because it's based on how helpful meldrob has been to the Kudzu community. Hard work This is SuwaneeLori's TrustRating, which is based on both the number of reviews SuwaneeLori has written, and how many other people have voted those reviews as "helpful." It's a way to quickly to determine the value of any single review or reviewer, because it's based on how helpful SuwaneeLori has been to the Kudzu community. You need to do this for yourself! Share: This is the first time in my life that I feel that I am making healthy, life-long changes in the way I live. While I am still in the process of my "transformation," I know that with Xtreme Transformations' expert help, I will get to my goal.	{ "pile_set_name": "Pile-CC" }
--- abstract: 'We use functional, Fréchet, derivatives to quantify how thermodynamic outputs of a molecular dynamics (MD) simulation depend on the potential used to compute atomic interactions. Our approach quantifies the sensitivity of the quantities of interest with respect to the input functions as opposed to its parameters as is done in typical uncertainty quantification methods. We show that the functional sensitivity of the average potential energy and pressure in isothermal, isochoric MD simulations using Lennard-Jones two-body interactions can be used to accurately predict those properties for other interatomic potentials (with different functional forms) without re-running the simulations. This is demonstrated under three different thermodynamic conditions, namely a crystal at room temperature, a liquid at ambient pressure, and a high pressure liquid. The method provides accurate predictions as long as the change in potential does not significantly affect the region in phase space explored by the simulation. The functional uncertainty quantification approach can be used to estimate the uncertainties associated with constitutive models used in the simulation and to correct predictions if a more accurate representation becomes available.' address: 'School of Materials Engineering, Birck Nanotechnology Center, Purdue University, West Lafayette, Indiana 47906, USA' author: - Samuel Reeve - Alejandro Strachan bibliography: - 'bibtex/Reeve-Strachan-2016\_main.bib' title: 'Error correction in multi-fidelity molecular dynamics simulations using functional uncertainty quantification' --- uncertainty quantification ,functional derivative ,molecular dynamics ,interatomic potential ,free energy calculation Introduction ============ Uncertainty quantification (UQ) is becoming increasingly important in predictive simulations of materials and devices [@Chernatynskiy2013]. While the majority of the early UQ work focused on solid and fluid mechanics, there is growing interest in applying and extending UQ techniques to simulations at the material level, including density functional theory [@Mortensen2005; @Anderson2012], molecular dynamics (MD) [@Rizzi2012p1; @Rizzi2013p1; @Angelikopoulos2013; @Karniadakis2015; @Patrone2016], and multiscale methods [@Koslowski2011; @Kim2013; @Vedula2013]. These efforts highlighted the importance of acknowledging uncertainties in model parameters, from measurement or averaging techniques, as well as intrinsic variability of the systems or processes under investigation. These studies, and most UQ work thus far, examined uncertainties in input parameters and specialized software packages have been developed for this task: examples include DAKOTA [@Adams2014], PUQ [@Hunt2015], and $\Pi$4U [@Hadjidoukas2015]. However, in many applications – especially those involving complex physics – accounting for uncertainty in parameters is not enough, as the functional forms of the constitutive models themselves are approximate. This is particularly true in materials modeling where lack of knowledge leads to unquantified or poorly quantified uncertainties. Examples of input functions with varying degrees of accuracy include exchange and correlation functionals used in density functional theory calculations [@Mortensen2005; @Aldegunde2016], interatomic potentials for molecular dynamics (MD) [@Rizzi2012p2; @Rizzi2013p2; @Farrell2015], generalized stacking faults used in dislocation dynamics [@Cao2015], and constitutive laws for micromechanical simulations. In this paper we use functional derivatives (FD), recently proposed as a mathematical framework to quantify uncertainties that arise from constitutive models used in simulations [@Strachan2013], to quantify and correct uncertainties that originate from the interatomic potential used in MD simulations. Functional uncertainty quantification (FUQ) can, in principle, be used to assess the uncertainties originating from approximate input constitutive laws, correct predictions if a more accurate function becomes available, and rank when and where to replace a low-fidelity model used in a simulation with one of higher fidelity in order to reduce prediction error by running additional simulations. This paper introduces a computationally efficient method to compute FDs in MD simulations involving two-body interatomic potentials, extending ideas from thermodynamic integration and free-energy perturbation methods [@Frenkel2001; @Chipot2007]. The FD quantifies how a quantity of interest (QoI) – in this case the total potential energy or pressure computed from an MD simulation in the canonical ensemble – depends on the input function, here the Lennard-Jones (LJ) two-body pair potential. We further show that the FD with respect to the LJ potential can be used to compute accurate correction to the potential energy and pressure for a family of pair potentials without re-running the simulation. This is true as long as the discrepancy between the potentials remains within reasonable bounds and the phase space explored by the system with the new potential is not significantly different from that of the original. The remainder of the paper is as follows. Section 2 describes the functional approach to UQ followed by simulation details and methods to calculate the functional derivative numerically in Section 3. In Section 4 we describe specific examples of error correction using FUQ with low and high-fidelity models. Sections 5 and 6 discuss results and conclude the paper. Functional uncertainty quantification ===================================== In general, a simulation predicts a quantity of interest, $Q$, given some set of input parameters $P_i$ and constitutive functions $f_j$, themselves functions of an independent variable $z$ and input parameters $N_k$: $$\label{eq:QoI} Q=Q({P_i},{f_j(z,{N_k})})$$ In the cases of interest here, $Q$ will be the time averaged potential energy or pressure and $f(z)$ the LJ potential as a function of interatomic distance used in the MD simulation. The most common form of UQ is concerned with uncertainty in simulation outputs arising from uncertainty in the input parameters. This approach, while very valuable, ignores the fact that the functional forms used as constitutive laws are, almost invariably, approximate and lead to errors in the simulation. To quantify uncertainties with respect to input functions we utilize functional derivatives (Fréchet derivatives) of the QoI with respect to the input functions. The FD can be written in differential form as: $$\label{eq:FD1} \frac{\delta Q[f]}{\delta f(z)}(z_i) = \lim_{\epsilon \to 0} \frac{Q[f(z) + \epsilon\cdot\delta(z-z_i)] - Q[f(z)]}{\epsilon}$$ This characterizes the functional sensitivity of the QoI with respect to the input function. The definition in Eq. \[eq:FD1\] uses the Dirac delta function as the functional variation; as we describe below, to calculate the functional derivative numerically for the MD simulations we use narrow Gaussian distributions centered at $z_i$. Besides quantifying uncertainties in the prediction given uncertain input functions, the functional derivative can be used to correct the error that arises from the use of a low-fidelity model $(f)$ if a higher-fidelity one $(g)$ becomes available. The correction is then obtained using the product of the functional sensitivity (the FD) and functional discrepancy $(g(z)-f(z))$. We call this product the functional error and the correction for the QoI is: $$\label{eq:correct} \Delta Q = \int \frac{\delta Q[f]}{\delta f(z)} \cdot (g(z)-f(z)) dz$$ In the absence of a high-fidelity model Eq. \[eq:correct\] can alternatively be used for uncertainty propagation by replacing the discrepancy with the uncertainty in $f(z)$ and taking the absolute value of the functional derivative [@Strachan2013]. This procedure returns a first order bound of the uncertainty in Q. Additionally, this equation can be used to rank high-fidelity simulations in order of their functional error to optimally reduce the error in the predicted QoI, recently demonstrated with calculation of the functional derivative for the restoring force in a multi-fidelity radio frequency MEMS switch simulation [@Strachan2013]. This functional derivative was used to rank model evaluations and minimize the necessary computational cost to maximize error correction in the simulation. In Section 3 we extend the formulation to a significantly more challenging problem: molecular dynamics simulations. Functional derivatives in molecular dynamics ============================================ Systems of interest and simulation details ------------------------------------------ We demonstrate the FUQ method in molecular dynamics simulations where the input function is the pairwise interatomic potential and the QoIs are the potential energy and pressure (long-time averages) of the system. We take the Lennard-Jones 12-6 potential as the low-fidelity input function: $$\label{eq:LJ} \phi_0 = 4\epsilon((\sigma/r)^{12}-(\sigma/r)^6)$$ and test the ability of FUQ to correct the prediction of the QoI for a family of high-fidelity potentials. The parameters for the low-fidelity LJ potential are designed to roughly describe copper $(\sigma=2.315$Å, $\epsilon=0.167 eV)$ [@Wolf1992], fit to the bulk melt temperature and room temperature lattice constant. We note that this is not an accurate potential for Cu as it ignores important many body effects critical to describe elastic constants and defect energetics. Also notable is the discrepancy of the liquid densities as compared to experiment [@Cahill1962]. However, the goal of the paper is to demonstrate the applicability of FUQ to an MD problem. In this spirit, the high-fidelity potentials are similarly designed for demonstration purposes only and do not represent a more accurate representation of an actual material. We construct seven pair potentials by additively modifying the LJ potential with sine functions in Table 1. This family of functions will be denoted Sine 1 to Sine 7. Name Modification function -------- ------------------------------------------ Sine 1 $0.44+0.46\sin(0.17(24.2+r))$ Sine 2 $-0.47\sin(-0.15(14+r))\cdot \exp(-r)$ Sine 3 $0.07\sin(1.2(-1.2+r))/r^2$ Sine 4 $-0.01+0.2\sin(0.3(14+r))\cdot \exp(-r)$ Sine 5 $0.7\sin(0.4(11+r))\cdot \exp(-r)$ Sine 6 $0.9\sin(0.4(11+r))\cdot \exp(-r)$ Sine 7 $1.1\sin(0.4(11+r))\cdot \exp(-r)$ : High-fidelity potential sine modification terms[]{data-label="tbl:sine"} A final high-fidelity model tested is the Morse potential, defined as the sum of two exponentials: $$\label{eq:Morse} \phi=D_0(e^{-2\alpha(r-r_0)} -2e^{-\alpha(r-r_0)})$$ We use $D_0=0.161 eV$, $\alpha=2.09$Å${}^{-1}$, and $r_0=2.62$Å to similarly roughly describe copper. For all potentials a smoothing function is used to ensure stable dynamics near the cutoff. The function is of fourth order to create potential energy and force curves that both smoothly tend to zero: $$\label{eq:smooth} s(r) = \frac{(\frac{(r - r_c)}{w})^4}{(1+\frac{(r - r_c)}{w})^4}$$ where $r_c$ is the cutoff distance and $w$ is the width of the smoothing. For all potentials the cutoff is 5.79Å ($2.5\sigma$, commonly used for LJ potentials) and smoothing width 1.5Å. Each potential curve is created by summing the base equation and the modification term and subsequently taking the product with the smoothing function. The force curve is then created with product rule differentiation of the potential. These potentials are shown in Figure \[fig:potentials\]. Each system consists of 500 atoms simulated under isothermal, isochoric conditions (canonical ensemble). Three physical states of the system were simulated: one solid at ambient temperature and pressure ($300 K$ with density of $9.02 g/cm^3$), one liquid slightly above the melt temperature at ambient pressure ($1300 K$ with density of $6.48 g/cm^3$) and another liquid at extreme temperature and pressure ($5000 K$ with density of $8.93 g/cm^3$, corresponding to $55 GPa$). All MD simulations were performed using the LAMMPS package [@Plimpton1995]. For each high-fidelity potential we performed 16 independent simulations, each 1 ns long, sufficient for good statistical sampling of the quantities of interest. For each low-fidelity potential, from which the functional derivatives were calculated, the total sample time was 64 ns, similarly from 64 independent simulations of 1 ns. The convergence of this sampling is shown in the supplementary material. Numerical functional derivatives and a perturbative approach for their calculation ---------------------------------------------------------------------------------- For the specific case of interest the functional derivative expression becomes: $$\label{eq:FD2} \frac{\delta Q[\phi]}{\delta \phi}(r_i) = \lim_{\epsilon \to 0} \frac{Q[\phi_0(r) + \epsilon\cdot\phi'(r-r_i)] - Q[\phi_0(r)]}{\epsilon}$$ where $Q[\phi]$ denotes the average QoI – the potential energy or pressure of the system – using interatomic potential $\phi$. The unmodified LJ potential is $\phi_0$ and $\phi'$ a normalized Gaussian perturbation centered at interatomic distance $r=r_i$ with width $\sigma$. The functional derivative in Eq. \[eq:FD2\] can be calculated by performing a set of simulations with the low-fidelity potential modified by perturbations of varying $\epsilon$ and computing a numerical derivative for each position $r_i$. These modified Lennard Jones potentials and resulting average potential energies as a function of size of the perturbation $\epsilon$ are shown in Fig. \[fig:calcFD\](a) and (b), respectively. However, this brute force approach is computationally very intensive considering that we may need to sample the functional derivative at 100 values of $r_i$. Even with only three values of $\epsilon$ for each separation distance one would need to perform 300 separate MD simulations. To alleviate the computational cost of the approach we now derive a perturbative approach to calculate the functional derivative that can be computed with little overhead with respect to the nominal simulation using the low-fidelity potential, $\phi_0$. At the heart of the calculation of the FD is the evaluation of canonical averages of the QoIs with the interatomic potential and a Gaussian perturbation. Recognizing that the modified Hamiltonian of the system can be additively decomposed into the kinetic energy, the original LJ potential energy and the functional variation (or perturbation) for these two-body potentials we can write the canonical ensemble average of quantity Q as: $$\label{eq:ensavg} \langle Q \rangle_H = \frac{\int Q \cdot e^{-\beta H_0} \cdot e^{-\beta H'}}{\int e^{-\beta H_0} \cdot e^{-\beta H'}}$$ where $H_0$ is the Hamiltonian with the LJ potential and $H'$ the potential energy resulting from the Gaussian perturbation following form from Eq. \[eq:FD2\]. Equation \[eq:ensavg\] can be re-written as the ratio between two canonical averages over the unmodified Hamiltonian by multiplying by additional factors of $\int e^{-\beta H_0}$ and rearranging: $$\label{eq:perturbative} \langle Q \rangle_H = \langle Q \cdot e^{-\beta H'} \rangle_{H_0} \cdot \frac{1}{\langle e^{-\beta H'} \rangle_{H_0}}$$ Since both canonical averages are over the unmodified potential only simulation with the low-fidelity potential is required. Therefore, computing the functional derivatives requires evaluating the Gaussian perturbation potentials on the trajectory obtained with the low-fidelity model. Such expressions are commonly used to compute free energies in thermodynamic integration and free energy perturbation approaches [@Straatsma1992; @Kollman1993]. Quantities for the canonical average in Eq. \[eq:perturbative\] are computed every 1 ps with a total of 48 ns of simulation time with the low-fidelity LJ potential, deemed well converged (see supplementary material). We evaluate these averages using a binned coordination number with a total of 2000 bins to compute $H'$ and $Q$ (as it contains contributions from the perturbation), described in more detail in the appendix. Use of the coordination number simply allows to further reduce computation and avoid modifying the MD code. Performing the calculation directly within the MD force loop with atomic positions would be equivalent excluding slight discrepancies from discretization. Using Eq. \[eq:FD2\] with the first term in the difference calculated using Eq. \[eq:perturbative\] we compute the functional derivative with respect to Gaussian perturbations centered at $r_i$ with width $\sigma = 0.1$ Å and height $\epsilon=\pm0.00075$ and $\pm0.00375$ eV. The perturbation width was chosen to minimize (localize) the perturbation while retaining sufficient sampling. The heights were similarly minimized, due to the difficulty of converging exponentially weighted averages, while ensuring a measurable effect from the perturbations. The numerical derivative is then evaluated by computing the slope of the QoI with respect to $\epsilon$ (Fig. \[fig:calcFD\](b)) at a set of interatomic separations ranging from zero past the potential cutoff in increments of $0.05$ Å. The thick blue lines in Figure \[fig:FD\] show the functional derivatives obtained in this manner for all physical conditions and both QoIs. These curves were averaged from multiple calculations of the FD with independent randomized samplings from the total of 64 ns of simulation time. The functional derivative displays significant information about the physics of the systems. The overall shapes correspond to the atomic shells as in the radial distribution function – notably more pointed for the solid case. At very low separation distances the FD goes to zero as atoms hit the soft-wall repulsion of the potentials; for the extreme liquid system the atoms occupy smaller separations. To assess the accuracy of the calculation the functional derivative was also computed at equally spaced values of $r_i$ using the brute force approach described above. For each value of $r_i$ we perform four MD simulations with varying perturbations (identical to those in the perturbative approach) added to the LJ potential as shown in Fig. \[fig:calcFD\](a) and obtain the functional derivative with the same numerical derivatives as the perturbative approach. For each separate perturbation the simulation was run for 16 ns (split between 16 independent systems). The results of the brute force approach are shown in red in Fig. \[fig:FD\]; the two methods of calculating the functional derivative are nearly identical with only small numerical discrepancies. Error correction using functional derivatives {#sec:results} ============================================= To demonstrate our approach we now use the functional derivative calculated perturbatively in the previous section to correct the potential energy and pressure predicted with the low-fidelity LJ potential assuming a more accurate function is available. As discussed in subsection 3.1, a family of seven high-fidelity potentials were created by modifying the LJ potential with sine functions; see Figure \[fig:potentials\] and Table \[tbl:sine\]. These results are discussed in sub-section \[sec:resultsSine\]; the results for the Morse potential are discussed in sub-section \[sec:resultsMorse\]. Corrections for sine modified potentials {#sec:resultsSine} ---------------------------------------- In order to use Eq. \[eq:correct\] we need, in addition to the functional derivative, the discrepancy function $(\phi_{HF} (r) - \phi_{LF} (r))$, the difference between the high and low-fidelity potentials. Figure \[fig:correct\] illustrates the functional derivative (a), the discrepancy (b), and the product of the two, the functional error (c), each as a function of interatomic distance for one case, the ambient liquid with modified potential Sine 1. These results are shown for each physical case and potential in the supplementary material. Note that the functional error goes to zero both for small and large values of $r$; at small $r$ it goes to zero following the functional derivative (due to steep repulsion that keeps atoms from coming close to one another), while for large distances the discrepancy goes to zero as both potentials tend to zero at the same cutoff. The functional error was numerically integrated using the trapezoid rule to obtain the total correction for the QoI. In order to verify these correction predictions we performed explicit MD simulations with the high-fidelity modified LJ potentials. Figure \[fig:results\] compares the potential energy (a) and pressure (b) differences explicitly simulated with low and high-fidelity potentials (gray) to the corrections obtained with FUQ (with colors matching those in Fig. \[fig:potentials\], as well as the hybrid LJ-Morse potential discussed in sub-section \[sec:resultsMorse\] in white). These results are shown in detail in Tables \[tbl:PE\] and \[tbl:P\] in the appendix. For almost all cases, the FUQ predictions are in excellent agreement with the direct simulations. Excluding only the Sine 6 and 7 potentials for the ambient liquid (discussed below) average error is 0.600% and 1.70% for potential energy and pressure, respectively. We stress that these very accurate corrections are obtained only making use of the the simulation with the unmodified LJ potential, no additional MD simulations are required. The ability of FUQ to correct the QoIs is impacted greatly by the degree of phase space overlap between the high and low-fidelity simulations. This can be shown simply by the overlap in histograms of probability distributions of differences in potential energy from the initial to final state, a common practice in free energy calculations [@Pohorille2010]. In this case, the states refer to the potential used and the distributions are taken from: $$\label{eq:hist0} \Delta U_0 = (U(\phi_{HF}, \Gamma_{LF}) - U(\phi_{LF}, \Gamma_{LF}))$$ $$\label{eq:hist1} \Delta U_1 = (U(\phi_{LF}, \Gamma_{HF}) - U(\phi_{HF}, \Gamma_{HF}))$$ where each term is the energy with potential $\phi$ and set of samples in phase space $\Gamma=(\mathbf{x_1}, ..., \mathbf{x_N})$ (each point dependent on the positions of the $N$ atoms) from the high or low-fidelity potential trajectory. Examples are shown in Fig. \[fig:hist\]. Lack of phase space overlap and difference in probability distributions is most significant for the the ambient liquid with the Sine 6 and 7 potentials, the same two cases with significantly larger error. Further inspection of the MD trajectory shows that the modified potential results in a structural transformation while the unmodified LJ does not. This is shown in snapshots included as insets in Fig. \[fig:hist\] comparing the atomic structures for the ambient liquid with Sine 1 and Sine 7: the liquid undergoes cavitation for Sine 7 (and to a lesser extent with Sine 5 and 6). Insets were created using the OVITO software package [@Stukowski2010]. Thus the low-fidelity LJ explores a vastly different region in phase space as compared to that of the high-fidelity Sine 7; however, even under such unfavorable conditions FUQ is able to provide some level of correction. In contrast, the solid cases have sharply peaked distributions with strong overlap and correspondingly highly accurate predictions, with the caveat of more difficult convergence of the results. Histograms for all physical cases and potentials are within the supplementary material. The degree of similarity of phase space exploration can be further summarized by plotting the average of $\Delta U_0$ against the average of $\Delta U_1$. The closer to slope of unity, the more significant the distribution overlap. Figure \[fig:histpoints\] gives results that agree with the histograms in Fig. \[fig:hist\] and supplementary material; namely, for cases where the explored phase space for the low and high-fidelity trajectories is less similar and there is little histogram overlap, the prediction error increases, particularly for the ambient liquid. Results in this figure for the Morse (gray symbols) and hybrid LJ-Morse (white) potentials are discussed in sub-section \[sec:resultsMorse\]. Correction for the Morse potential and hybrid potential calculations {#sec:resultsMorse} -------------------------------------------------------------------- Predicting properties for the Morse potential from LJ further highlights the challenge of attempting to correct a prediction made with a low-fidelity model. In this case the discrepancy between the two models is very large for short interatomic distances, leading to near zero phase space overlap and an inaccurate FUQ prediction for all physical cases. The red line in Figure \[fig:hybrid\] shows this discrepancy as a function of interatomic separation with the functional derivatives from both liquid conditions in blue to demonstrate the sensitivity to changes in the potential at these distances. The short range repulsion is described with an exponential for Morse while LJ uses an inverse power of 12. Thus the discrepancy between the two potentials diverges for short distances and the functional derivative correction, being first order, produces extremely large errors. These results are therefore omitted from Figure \[fig:results\]. Our approach can, nevertheless, be useful in such circumstances, but the high-fidelity model cannot be fully replaced by the low-fidelity one. Instead, we create a hybrid potential in Eq. \[eq:hybrid\] that smoothly switches from the low-fidelity LJ to the high-fidelity Morse between 2.8 and 2.4Å using error functions, leading to a discrepancy of reasonable magnitude shown in green in Figure \[fig:hybrid\]. $$\label{eq:hybrid} \phi_{Hybrid} = \begin{cases} \phi_{LJ}(r) & r\geq 2.8 \\ \phi_{LJ}(r)\cdot [B(r)+0.5] + \phi_{Morse}(r)\cdot [-B(r)+0.5] & 2.8 > r > 2.4 \\ \phi_{Morse}(r) & 2.4 \geq r \\ \end{cases}$$ $$\label{eq:erf} B(r) = 0.5\operatorname{erf}(8(r-2.6))$$ With the hybrid potential in Eq. \[eq:hybrid\] the high-fidelity model is used only where necessary. This is similar in spirit to adaptive sampling methods in multi-scale simulations, with examples in the literature [@Knap2008; @Barton2011; @Roehm2015] and codes available: the Co-design Embedded Visco-Plasticity Proxy Application (CoEVP) [@Dorr2014] and the Co-design Heterogeneous Multiscale Method Proxy Application (CoHMM) [@RouetLeduc2014]. It is then possible to use FUQ to correct a low-fidelity simulation run with this hybrid potential to the result with the high-fidelity Morse by using the discrepancy between the two potentials and the functional derivative of the hybrid potential. The hybrid potential reduces the discrepancy and the functional approach provides an accurate correction for all cases, as shown with the white bars in Figure \[fig:results\]. The solid case correction shows an additional example of increased error, again due to poor overlap in explored phase space between the two potentials (see supplementary material). Even with these significantly different systems FUQ provides the majority of the necessary correction. Further, all predictions for Morse from the hybrid potential (white symbols) lie near the unity line in Fig. \[fig:histpoints\] (describing good agreement between the phase space of each trajectory) in contrast to Morse from LJ (gray symbols), furthest from the line. We note that the high-fidelity model needs to be used during the actual simulation; however, only approximately 12% of the atomic force calculations fall in the range requiring the high-fidelity model. Thus, if the high-fidelity model was significantly more intensive than the low-fidelity the methodology would still greatly reduce computational cost. Discussion ========== The perturbative method to obtain the functional derivatives described here is similar to techniques in free energy methods: free energy perturbation and thermodynamic integration [@Bash1987; @Karplus1990]. One subset of these methods most comparable to FUQ and often used in biology simulations, referred to as computer alchemy, is utilized to calculate free energy changes along non-physical paths as potentials are slowly turned on or off for the various molecules or solvents of interest [@Gumbart2012; @He2014; @Wescott2002; @Lawrenz2012]. These methods share with the work described here the need to sample from the phase space trajectory of an initial state (often a simple reference state for free energy calculations, e.g. the Einstein crystal), ensure that phase space is not too dissimilar to that of the final state of interest, and to converge exponentially weighted averages. However, while free energy methods generally focus on a single path from initial to final state (or a bidirectional path), using FUQ, once the functional derivative is calculated for a given low-fidelity model, the corrections can be made with respect to any other high-fidelity model as long as minimum conditions are satisfied. If the low-fidelity simulation does not explore the regions of phase space relevant for the high-fidelity potential at the conditions of interest the results will be poor; this is most striking when switching potentials results in a structural phase transition. This phase space overlap should be checked as demonstrated here to ensure meaningful results as with free energy methods. Additionally, the functional derivative correction can only be used with a functional discrepancy such that its effect can be described to first order. We also note that the perturbative approach used here is applicable only to input functions that appear linearly in the Hamiltonian so the perturbation can be separated additively. This is not a general limitation of FUQ but of the specific approach used here to obtain the functional derivatives. This work demonstrates FUQ in equilibrium simulations. Continuing work should include investigation of functional derivatives in non-equilibrium processes as an analog of the relationships between free energy perturbation and non-equilibrium work methods in free energy calculations. The method can be generally used in equilibrium MD simulations and numerous other physics problems including multi-scale simulations. Ongoing investigations will include using FUQ to correct predictions in solid mechanics with the plasticity model as the input constitutive law. An important advantage of FUQ over uncertainty propagation in parameters is that it enables changes in the actual functional forms used in the simulation. In our example, we are not limited to Lennard-Jones potentials with different parameters but can change the shape of the potential (with the limitations discussed above). Conclusions =========== In summary we demonstrated the ability to calculate functional derivatives of a quantity of interest predicted by a non-trivial physics simulation with respect to its input laws. This information can be used to quantify the uncertainties originating in the simulation due to the use of the input function or to correct the prediction if a more accurate model becomes available. We developed a computationally efficient approach to compute the functional derivative in a MD simulations performed using the Lennard-Jones potential and shows that this information can be used to infer thermodynamic properties corresponding to various other potentials without re-running the simulation. The functional uncertainty quantification approach is quite generally applicable and we believe it will be useful to quantify uncertainties in a variety of materials models. Thermodynamic quantities using coordination number ================================================== The calculation of the functional derivative using the perturbative approach (Eq. \[eq:FD2\] and \[eq:perturbative\]) is expanded upon here, beginning with the contribution to the Hamiltonian from the perturbation. This quantity can be directly calculated with a sum over all pairs of atoms as the potential energy in any MD simulation: $$\label{eq:PEall} H' = \sum_{i<j} \phi'(r_{ij})$$ This would require modification of the MD code to calculate this quantity within the force loop or summing over a saved atomic trajectory. This expression can be replaced: $$\label{eq:PEcoord} H' = \frac{N}{2} \sum_{k} \phi'(r_k) \cdot c(r_k)$$ where $c(r)$ is the average coordination number at a given separation distance $r$, discretized into $k$ bins and $N$ the number of atoms. This is neither invasive to the code, nor requires significant storage or computation past the low-fidelity simulation. With the potential energy as the QoI, Q is simply the sum of Eq. \[eq:PEcoord\] and the low-fidelity simulation potential energy. For the pressure we use the virial expression (without the small ideal gas contribution as it is already present in the low-fidelity pressure): $$\label{eq:Pallvec} P' = \frac{1}{3V}\sum_{i<j} \textbf{f}_{ij} \textbf{r}_{ij}$$ Because we examine cases of two-body central forces this can be simplified: $$\label{eq:Pall} P' = \frac{1}{3V}\sum_{i<j} f(r_{ij})r_{ij}$$ and with the same motivations as above, we rewrite in terms of the coordination number, again with $k$ bins in separation distance: $$\label{eq:Pcoord} P' = \frac{N}{2} \frac{1}{3V}\sum_k f(r_k)\cdot r \cdot c(r_k)$$ This quantity, added to the low-fidelity simulation pressure, provides Q in Eq. \[eq:perturbative\] for the QoI pressure. Correction results ================== Tables \[tbl:PE\] and \[tbl:P\] show full results for all physical conditions for potential energy and pressure, respectively. Figure \[fig:results\] compares columns $\Delta Q^{Sim}$ and $\Delta Q^{FUQ}$. All results here are calculated with respect to the LJ low-fidelity potential, except the rows marked with (H). Those cases use the low-fidelity hybrid LJ-Morse potential. Temp. Potential $Q_{LF}$ $Q_{HF}$ $Q_{LF} + \Delta Q^{FUQ}$ $\Delta Q^{Sim}$ $\Delta Q^{FUQ}$ $\Delta Q$ % Error ------- ----------- ---------- ---------- --------------------------- ------------------ ------------------ -------------------- (K) - - 300 Sine 1 -1.08 -1.28 -1.27 -0.197 -0.196 0.456 300 Sine 2 -1.08 -0.928 -0.927 0.151 0.152 0.784 300 Sine 3 -1.08 -1.03 -1.03 0.0518 0.0522 0.793 300 Sine 4 -1.08 -1.31 -1.31 -0.235 -0.235 0.0132 300 Sine 5 -1.08 -1.33 -1.34 -0.256 -0.259 0.988 300 Sine 6 -1.08 -1.41 -1.41 -0.330 -0.333 0.993 300 Sine 7 -1.08 -1.48 -1.49 -0.403 -0.407 0.995 300 Morse -1.08 -0.998 -1.02 0.0804 0.0628 21.9 300 Morse (H) -1.05 -0.998 -1.00 0.0552 0.0520 5.89 1300 Sine 1 -0.704 -0.850 -0.850 -0.146 -0.146 0.0158 1300 Sine 2 -0.704 -0.602 -0.601 0.102 0.103 1.23 1300 Sine 3 -0.704 -0.666 -0.666 0.0377 0.0379 0.588 1300 Sine 4 -0.704 -0.867 -0.868 -0.164 -0.164 0.160 1300 Sine 5 -0.704 -0.878 -0.876 -0.174 -0.172 1.08 1300 Sine 6 -0.704 -0.956 -0.925 -0.252 -0.221 12.1 1300 Sine 7 -0.704 -1.03 -0.974 -0.330 -0.271 18.0 1300 Morse -0.704 -0.655 -0.662 0.0485 0.0416 14.3 1300 Morse (H) -0.703 -0.673 -0.673 0.0295 0.0295 0.0295 5000 Sine 1 -0.398 -0.598 -0.598 -0.200 -0.200 0.136 5000 Sine 2 -0.398 -0.243 -0.241 0.155 0.157 0.896 5000 Sine 3 -0.398 -0.346 -0.345 0.0524 0.0527 0.477 5000 Sine 4 -0.398 -0.636 -0.637 -0.238 -0.239 0.441 5000 Sine 5 -0.398 -0.663 -0.665 -0.265 -0.267 0.932 5000 Sine 6 -0.398 -0.738 -0.741 -0.340 -0.343 0.959 5000 Sine 7 -0.398 -0.814 -0.818 -0.416 -0.420 1.01 5000 Morse -0.398 -0.321 -0.393 0.0774 0.00547 93.1 5000 Morse (H) -0.366 -0.320 -0.320 0.0454 0.0455 0.376 : Comparison of potential energy correction from functional derivatives and direct simulation.[]{data-label="tbl:PE"} Temp. Potential $Q_{LF}$ $Q_{HF}$ $Q_{LF} + \Delta Q^{FUQ}$ $\Delta Q^{Sim}$ $\Delta Q^{FUQ}$ $\Delta Q$ % Error ------- ----------- ---------- ---------- --------------------------- ------------------ ------------------ -------------------- (K) - - 300 Sine 1 -0.116 -3.37 -3.25 -3.26 -3.13 3.89 300 Sine 2 -0.116 2.69 2.70 2.81 2.81 0.279 300 Sine 3 -0.116 0.514 0.538 0.630 0.654 3.75 300 Sine 4 -0.116 -4.12 -4.05 -4.01 -3.94 1.73 300 Sine 5 -0.116 -5.03 -5.07 -4.91 -4.95 0.763 300 Sine 6 -0.116 -6.43 -6.48 -6.32 -6.37 0.792 300 Sine 7 -0.116 -7.83 -7.90 -7.72 -7.78 0.805 300 Morse -0.116 1.43 -1.31 1.54 -1.19 177 300 Morse (H) 0.491 1.27 1.49 0.781 0.998 27.7 1300 Sine 1 0.129 -1.12 -1.13 -1.25 -1.26 1.44 1300 Sine 2 0.129 1.37 1.36 1.24 1.23 0.498 1300 Sine 3 0.129 0.563 0.562 0.434 0.433 0.219 1300 Sine 4 0.129 -1.58 -1.62 -1.71 -1.75 2.34 1300 Sine 5 0.129 -1.87 -2.03 -2.00 -2.16 7.70 1300 Sine 6 0.129 -1.75 -2.65 -1.88 -2.77 47.3 1300 Sine 7 0.129 -1.74 -3.26 -1.87 -3.391 81.5 1300 Morse 0.129 0.0733 -0.359 -0.0558 -0.488 774 1300 Morse (H) 0.124 0.469 0.463 0.344 0.338 1.68 5000 Sine 1 54.4 51.6 51.6 -2.77 -2.77 0.0187 5000 Sine 2 54.4 57.1 57.1 2.72 2.74 0.905 5000 Sine 3 54.4 55.1 55.1 0.7413 0.750 1.17 5000 Sine 4 54.4 50.6 50.6 -3.80 -3.81 0.161 5000 Sine 5 54.4 49.6 49.5 -4.81 -4.84 0.704 5000 Sine 6 54.4 48.2 48.2 -6.18 -6.23 0.845 5000 Sine 7 54.4 46.9 46.8 -7.53 -7.61 1.12 5000 Morse 54.4 39.8 36.8 -14.6 -17.5 20.1 5000 Morse (H) 39.0 39.8 39.8 0.796 0.794 0.279 : Comparison of pressure correction from functional derivatives and direct simulation.[]{data-label="tbl:P"} Acknowledgments {#acknowledgments .unnumbered} =============== This research was supported by the US Department of Energy (DOE), Office of Advanced Scientific Computing Research (ASCR) through the Exascale Co-Design Center for Materials in Extreme Environments (ExMatEx, exmatex.org). Computational resources of nanoHUB.org are gratefully acknowledged.	{ "pile_set_name": "ArXiv" }
Q: How to get the SQL error origin of an UnexpectedRollbackException I have a rollback exception with hibernate on my service "duplicateContract" Caused by: org.springframework.transaction.UnexpectedRollbackException: JTA transaction unexpectedly rolled back (maybe due to a timeout); nested exception is javax.transaction.RollbackException at org.springframework.transaction.jta.JtaTransactionManager.doCommit(JtaTransactionManager.java:1031) at org.springframework.transaction.support.AbstractPlatformTransactionManager.processCommit(AbstractPlatformTransactionManager.java:732) at org.springframework.transaction.support.AbstractPlatformTransactionManager.commit(AbstractPlatformTransactionManager.java:701) at org.springframework.transaction.interceptor.TransactionAspectSupport.commitTransactionAfterReturning(TransactionAspectSupport.java:321) at org.springframework.transaction.interceptor.TransactionInterceptor.invoke(TransactionInterceptor.java:116) at org.springframework.aop.framework.ReflectiveMethodInvocation.proceed(ReflectiveMethodInvocation.java:171) at org.springframework.aop.framework.JdkDynamicAopProxy.invoke(JdkDynamicAopProxy.java:204) at $Proxy128.duplicateContracts(Unknown Source) at com.test.server.rpc.SrvContractImpl.duplicateContracts(SrvContractImpl.java:699) at sun.reflect.NativeMethodAccessorImpl.invoke0(Native Method) at sun.reflect.NativeMethodAccessorImpl.invoke(NativeMethodAccessorImpl.java:39) at sun.reflect.DelegatingMethodAccessorImpl.invoke(DelegatingMethodAccessorImpl.java:25) at java.lang.reflect.Method.invoke(Method.java:597) at com.google.gwt.user.server.rpc.RPC.invokeAndEncodeResponse(RPC.java:561) ... 34 more Caused by: javax.transaction.RollbackException at org.objectweb.jotm.TransactionImpl.commit(TransactionImpl.java:329) at org.objectweb.jotm.Current.commit(Current.java:485) at org.springframework.transaction.jta.JtaTransactionManager.doCommit(JtaTransactionManager.java:1028) ... 47 more The problem is, I just can't debug that, there is an error with the persisted object somewhere but I have no clue ( it's not a timeout or missing @Transactional ). How can I get more details for this exception ? ( maybe somewhere in oracle log ? but where ? ). A: I checked the JOTM source code and, to my surprise, they don't propagate the original exception. try { propagateCtx = false; term.commit(true); propagateCtx = true; } catch (TransactionRolledbackException e) { Current.getCurrent().forgetTx(getXid()); if (TraceTm.jta.isDebugEnabled()) { TraceTm.jta.debug("Commit distributed transaction -> rolled back!"); } localstatus = Status.STATUS_ROLLEDBACK; throw new RollbackException(); } ... The JOTM project development seems to have stopped (last two releases adate back to 2006 and 2010), so you should better check Narayana, Atomikos or Bitronix.	{ "pile_set_name": "StackExchange" }
Contents As with many ancient towns in this mountainous region of southern Italy, Tocco Caudio was built on a promontory ridge. Tocco Caudio's ridge is fairly small and somewhat isolated. This arrangement made the town easily defensible, while having ready access to ridge-top roads along which a traveller would not need to cross any rivers. Also, as was typical with medieval development, the town is fairly compact with narrow streets. In the 20th century the town layout, previously beneficial for the inhabitants, became a hindrance, as most of the core of Tocco Caudio was fairly inaccessible to automobiles. After going up a short, steep hill, one could drive a car only along one part of the main street. In other towns in the province, [Sant'Agata Dei Goti] being a good example, many houses and shops in the old town areas are now vacant due to their inconvenience. Many new homes tend to be built around the old town centers, as there is no need to stay within the old defensive walls. In 1980 and 1981, earthquakes damaged much of the old historical habitat of Tocco Caudio. Rather than rebuild the historic town, the citizens were forced unwantedly to completely abandon it and resettle around the ridge. Today there are essentially two Tocco Caudios: an empty old town and a new town above it in a location called Friuni. The settlers there have never felt this in their town, and the loss of the historical town still lies in the memories of all, as if having lost the roots of the past, and having never planted the roots of the future and thus a population with no real identity. Anything of value from the historic center was stolen throughout the following years of the earthquake, eyes that should have been vigil in the control of such mishaps went blind, ears deaf and tonques silent, the final result today is reality a[ghost town]. Most buildings are derelict; the church has lost its roof, although the brick belltower and the incredible stone spiral staircase to the bellfry are in excellent condition. Fortunately the local and provincial administration from the year 2000 have managed to receive government grants to rebuild the old church, mainly to resemble a sort of historical landmark, as if to erect and let emerge a flame over an empty graveyard, as sort of lighthouse, to evoke not danger, but a light of hope and goodwill to renew and start a new era for all.	{ "pile_set_name": "Pile-CC" }
Wednesday, February 24 Grilled salmon is one of my very favorites. Every now and then I have a dream that I go to Alaska or Canada, reel in one of these beauties and grill it right there over an open flame! (no grizzlies I hope!) Actually I think this is Atlantic salmon but the visual is the same! There is an abundance of recipes for marinades, rubs and sauces for salmon. Right now I am into very simple. I let the fish do the talking - it is really all you need. Grilled Salmon by ann west salmon fillet cut into individual servings * see below olive oil rub on both sides of fish fresh lemon juice - squeeze this over your fish salt and pepper - generously crack on both sides herbs - your choice or omit - above I added a little fresh dill Grilling I like cutting the fillet into individual pieces for grilling. I feel that I have more control over the cooking and it is so simple to serve. Grill skin side DOWN first on medium heat (coals or gas). Leave it on until it tells you it is ready (it should not stick and be easy to move). 6 minutes or so. Flip to the flesh side and cook until done to your liking.	{ "pile_set_name": "Pile-CC" }
Circadian rhythm of autophagy proteins in hippocampus is blunted by sleep fragmentation. Autophagy is essential for normal cellular survival and activity. Circadian rhythms of autophagy have been studied in several peripheral organs but not yet reported in the brain. Here, we measured the circadian rhythm of autophagy-related proteins in mouse hippocampus and tested the effect of sleep fragmentation (SF). Expressions of the autophagy-related proteins microtubule-associated protein 1 light chain 3 (LC3) and beclin were determined by western blotting and immunohistochemistry. Both the hippocampal LC3 signal and the ratio of its lipid-conjugated form LC3-II to its cytosolic form LC3-I showed a 24 h rhythm. The peak was seen at ZT6 (1 pm) and the nadir at ZT16 (1 am). The LC3 immunoreactivity in hippocampal CA1 pyramidal neurons also distributed differently, with more diffuse cytoplasmic appearance at ZT16. Chronic SF had a mild effect to disrupt the 24 h rhythm of LC3 and beclin expression. Interestingly, a greater effect of SF was seen after 24 h of recovery sleep when LC3-II expression was attenuated at both the peak and trough of circadian activities. Overall, the results show for the first time that the hippocampus has a distinct rhythm of autophagy that can be altered by SF.	{ "pile_set_name": "PubMed Abstracts" }
Making Democracies Resilient to Modern Threats Seminar organized by the Fulbright Finland Foundation in cooperation with the Finnish Prime Minister’s Office, the Finnish Ministry for Foreign Affairs, the United States Department of State, and hosted by the Metropolia University of Applied Sciences. Join the discussion on Twitter with #ReDe Democratic societies, institutions, and individual citizens are facing entirely new challenges in the modern era. Today’s threats can include network-based intrusions, misinformation and ‘fake news,’ influence campaigns, and many more. These threats have the potential to disrupt economic activity and development, threaten the national security of like-minded nations, jeopardize individual privacy, and sow mistrust among citizens towards their national and collective democratic institutions. The seminar will seek to highlight a wide range of threats that democracies face today and may face tomorrow as well as provide strategies for institutions and individuals to understand and deal with these threats. General themes presented will touch upon how to recognize disinformation and influence campaigns, media literacy and the role of media organizations and individual journalists, security in digital spaces, and positive examples of how democracies are currently countering these threats. 13:15 Keynote: “Vulnerable-Resilient Democracy: The Duality of Cybersecurity”Richard Harknett, Professor of Political Science, University of Cincinnati, 2017 Fulbright Professor in Cyber Studies at Oxford University "Structural Weaknesses in Modern Democracies"Matthew A. Baum, Marvin Kalb Professor of Global Communications and Professor of Public Policy at Harvard University's John F. Kennedy School of Government and Department of Government "How Social Media Platforms Are Used to Interfere with Democratic Processes"Jonathan Albright, Director of Research, Tow Center for Digital Journalism, Columbia University "Rumors, Truths, and Reality: Political Misinformation in the Modern Day"Adam Berinsky, Mitsui Professor of Political Science and Director, MIT Political Experiments Research Lab, Massachusetts Institute of Technology In addition to the public seminar, there are two special events: The on-site logistics at the Grand Festive Hall for this seminar are provided by students of the Metropolia University of Applied Sciences. The organizers wish to extend their sincere thanks to the conference assistants of the Managerial Communication course.	{ "pile_set_name": "Pile-CC" }
All data are available from published studies which are publicly available. Details of each study from which data were drawn for the current meta-analysis are included within the paper and supporting files. Introduction {#sec001} ============ Broad research has found evidence of the relationship between insecure attachment style and mental disorders, including Eating Disorders (EDs) \[[@pone.0213099.ref001]--[@pone.0213099.ref003]\]. It is accepted that individuals with EDs have a higher prevalence of insecure attachment than healthy controls as it has been unanimously established in previous reviews \[[@pone.0213099.ref003]--[@pone.0213099.ref006]\]. In addition, insecure attachment seems to be a risk factor for the subsequent emergence of disordered eating in non-clinical populations \[[@pone.0213099.ref007],[@pone.0213099.ref008]\]. In the last two decades several researchers have explored the connection between insecure attachment and eating pathology at both clinical and sub-clinical level, in cross-sectional \[[@pone.0213099.ref009],[@pone.0213099.ref010]\] and longitudinal studies \[[@pone.0213099.ref011],[@pone.0213099.ref012]\]. Identifying the mechanisms by which insecure attachment may increase the vulnerability to EDs across the life span may offer novel perspectives for clinical assessment, prevention and treatment \[[@pone.0213099.ref007],[@pone.0213099.ref013]\]. Nevertheless, despite the great interest and growing number of studies on this topic, to date there has not been any systematic synthesis of this literature. Insecure attachment and vulnerability to eating pathology {#sec002} --------------------------------------------------------- Attachment is an emotional long-lasting bond that infants develop with the main caregivers over the first years of life \[[@pone.0213099.ref014]\]. Based on this early caregiving environment, children develop representations about themselves and about the social world, known as Internal Working Models, which will guide their psychosocial functioning across life span \[[@pone.0213099.ref015],[@pone.0213099.ref016]\]. When primary attachment figures are emotionally available, consistent and responsive to the child's needs, they provide a solid base for exploring the world, where the self is viewed as valued and loved and, represent a safe haven where the child can reach comfort and protection in times of distress (\[[@pone.0213099.ref017]--[@pone.0213099.ref019]\]. Repetitive attachment-related experiences with a sensitive caregiver also contribute to the development of adaptive emotion regulation skills \[[@pone.0213099.ref020]\]. In contrast, insecure attachment relationships do not provide stable assistance and support to facing threating situations \[[@pone.0213099.ref021]\]. As a result, insecurely attached children develop dysfunctional cognitive patterns alongside with inconsistent emotion regulation abilities that lead them to interact either restricting (avoidant attachment) or exaggerating (anxious attachment) their need for comfort, security and proximity to their attachment figures \[[@pone.0213099.ref014],[@pone.0213099.ref020]\]. In this respect, anxiety and avoidance can be conceptualized as two dimensions aligned as opposite ends of a continuum in which different styles of insecure attachment can be located \[[@pone.0213099.ref022],[@pone.0213099.ref023]\]. Broad research guided by the theory of attachment has established clear associations between insecure attachment style and the expression and maintenance of unhealthy eating attitudes and behaviors, at both clinical and sub-clinical level \[[@pone.0213099.ref005],[@pone.0213099.ref007],[@pone.0213099.ref008]\]. Nevertheless, the literature inquiring into the association between different attachment styles and specific ED subtypes remains inconclusive \[[@pone.0213099.ref003],[@pone.0213099.ref007]\]. Consequently, current research tends to examine the link between insecure attachment (regardless of a specific style) and the severity of eating symptomatology across diagnosis \[[@pone.0213099.ref002],[@pone.0213099.ref013]\]. Similarly, in non-clinical samples there is evidence for the association between insecure attachment and premorbid symptoms such as higher weight concerns \[[@pone.0213099.ref024]\], body dissatisfaction \[[@pone.0213099.ref025],[@pone.0213099.ref026]\], restrictive eating \[[@pone.0213099.ref027]\] and binge eating \[[@pone.0213099.ref028]\] supporting therefore the hypothesis that eating disorder symptoms can be the manifestations of the psychological and emotional processes developed from insecure attachment relationships. However, an insecure attachment is not a sufficient cause for the development of psychopathology \[[@pone.0213099.ref019]\], but in most cases this influence may be indirectly conditioned by the concurrence of different variables that can modify the early attachment experiences \[[@pone.0213099.ref029],[@pone.0213099.ref030]\]. In this regard, research suggests that the relationship between insecure attachment and eating disorder symptoms may be explained by multiple mediating mechanisms \[[@pone.0213099.ref003],[@pone.0213099.ref019]\]. In particular, studies hint towards the potential role of problematic emotional regulation, negative affect, maladaptive perfectionism and body dissatisfaction explaining how attachment insecurity might put someone at risk for ED at young age \[[@pone.0213099.ref008],[@pone.0213099.ref031]\] or might maintain ED symptoms \[[@pone.0213099.ref005],[@pone.0213099.ref013]\]. The understanding of these intermediate variables driving from early insecure experiences to the symptomatic expression of eating pathology across time provides new insight into this topic. As noted previously, insecurely attached people are more likely to report negative feelings about the self, experience interpersonal difficulties and use maladaptive coping strategies, such as suppress/avoid (i.e., deny stress or divert attention, consistent with avoidant style) or accentuate emotional experiences (i.e., rumination or self-blame, consistent with anxious style), to deal with distress \[[@pone.0213099.ref021],[@pone.0213099.ref032]\]. Collectively, it can be understood that insecurely attached people in their hopes to reduce negative feelings about themselves turn to eating symptoms such as dieting (to reach perfect body image), binge eating (to increase mood and get distracted) and purging (to compensate the negative feelings of breaking the diet and avoid gaining weight) \[[@pone.0213099.ref021],[@pone.0213099.ref033],[@pone.0213099.ref034]\]. Due to the lack of functionality of these strategies, negative affect remains and keeps the cycle activated, triggering the symptomatology every time the person has to face distress \[[@pone.0213099.ref007]\]. Previous reviews and aims for the current study {#sec003} ----------------------------------------------- Since the publication of the review by Ward et al. \[[@pone.0213099.ref006]\], the number of studies focused on the mechanisms whereby the insecure attachment might trigger the development of eating symptomatology has considerably increased. In fact, some recent research pointed out to specific mechanisms linking insecure attachment and the expression of disordered eating that shed light into the processes involved in the development of the symptoms \[[@pone.0213099.ref008],[@pone.0213099.ref013]\]. On the other hand, statistical analyses used to determine how or why an independent variable transmits its effect on a dependent variable, namely the hypothesis of mediation, have experienced an important development in the last 20 years \[[@pone.0213099.ref035]--[@pone.0213099.ref037]\]. In spite of the advances and increased interest about the mediating mechanisms through which insecure attachment confers vulnerability to the development of ED symptoms, no study has systematically reviewed or measured the impact of these mediators to date \[[@pone.0213099.ref003],[@pone.0213099.ref007]\]. In order to overcome these gaps, we aim at identifying the pathways through which insecure attachment may lead to eating psychopathology and at quantifying the size effect of the mediators through a meta-analysis. Taking into account the prior literature, we expect that emotional dysregulation and depressive symptoms along with other psychological variables, such as body dissatisfaction and perfectionism, will mediate the relation between attachment and ED psychopathology. This knowledge not only will contribute to a better understanding about specific factors that could play a role in the maintenance of EDs, but will also provide empirical evidence for existing theories and for formulation of new hypotheses for treatment targets \[[@pone.0213099.ref007],[@pone.0213099.ref038],[@pone.0213099.ref039]\]. Method {#sec004} ====== Registration of systematic review and meta-analysis {#sec005} --------------------------------------------------- The protocol for the present study was registered with the PROSPERO international prospective register of systematic reviews (CRD42017076807) and can be accessed at <http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42017076807>. Our review is reported in accordance with the PRISMA \[[@pone.0213099.ref040]\] ([S1 Table](#pone.0213099.s002){ref-type="supplementary-material"}). Search strategy {#sec006} --------------- A systematic literature search was performed on the following databases: Medline, Pubmed, WOS (Web of Science), Scopus, PsycINFO, EMBASE and Conference Proceedings Citation Index-Science (CPCI-S) and Social Science & Humanities (CPCI-SSH) up to January 2019. The initial search terms used as keywords were: \[(attachment style OR attach\) AND (eating disorder OR eating symptom\)\]. Besides, to focus the search identifying studies reporting on mediational mechanisms, a tailored search strategy was conducted: \[(attachment style OR attach\* OR attachment) AND (eating disorder\* OR eating symptom\* OR eating psycho\* OR \"disordered eating\") AND (mediat\* OR indirect OR \"structural equation modeling\" OR \"structural equation modelling\" OR \"SEM\" OR (Baron AND Kenny) OR Mackinnon OR \"product of coefficient\" OR \"difference in coefficient\" OR sobel OR \"causal pathway\" OR intermediate OR \"indirect effect\" OR mechanism)\]. Reference lists of included studies, as well as recent reviews in the field, were scanned for any additional relevant studies. Inclusion/exclusion criteria {#sec007} ---------------------------- For inclusion in this study, the studies had to meet the following criteria: (1) published in a peer-reviewed journal prior to January 2019; (2) reported on mediators between attachment style (towards physical person) and eating disorder symptoms; (3) used standardized measures (either through self-report, administered questionnaires or structured interviews) of attachment style, eating pathology and mediating variables such as: ECR (Experiences in Close Relationships), EAT (Eating Attitudes Test), EDI (Eating Disorder Inventory) or EDEQ (Eating Disorder Examination Questionnaire); (4) used a formal mediation analysis (e.g. Baron and Kenny's causal steps of mediation, structural equation modelling) or significance tests of mediation (e.g. Sobel test, bootstrapping); (5) carried out with participants at any age from clinical (by criteria DSM-IV, DSM-IV-TR, or DSM-5) or non-clinical samples (individuals reporting symptoms of EDs but who endorse subthreshold levels of one or more symptoms \[[@pone.0213099.ref041]\]) and (6) written in English, Spanish, German or French. In order to perform the meta-analysis, additionally to these inclusion criteria, we required at least two studies per mediator. Patients with obesity and comorbid ED were excluded. We did not consider papers exploring perceived quality of relationships or attachment as a mediator since the focus of our study is to understand attachment as an independent variable. Study selection {#sec008} --------------- Preliminary screening of the studies obtained by the systematic search was performed by the main author (LCG). Two co-authors (LCG and CS) reviewed all titles and abstracts, excluded studies that did not address mediational analysis, and independently examined each full article to determine final inclusion or exclusion. Reasons for exclusion of full texts were recorded and documented in a PRISMA flow diagram ([Fig 1](#pone.0213099.g001){ref-type="fig"}). Discordances on inclusion or exclusion of articles were analyzed, and disagreements were resolved via discussion. ![Flowchart for search strategy.\ Fig 1 represents the flow information through the different four phases of the systematic review. Following PRISMA guidelines, a total of 24 studies were eligible to be included in the systematic review and 21 model were included to be meta-analyzed.](pone.0213099.g001){#pone.0213099.g001} Data extraction {#sec009} --------------- Two data extraction templates were specifically developed for the current review. First, basic descriptive information about the study was collated (Tables [1](#pone.0213099.t001){ref-type="table"} and [2](#pone.0213099.t002){ref-type="table"}). A second template was used to extract the required data for the meta-analysis. The data extracted and coded are displayed in [S2 Table](#pone.0213099.s003){ref-type="supplementary-material"}. Up to 3 e-mail requests were also sent to the corresponding author to obtain any unpublished data necessary to perform the meta-analysis \[[@pone.0213099.ref011],[@pone.0213099.ref042]--[@pone.0213099.ref045]\]. In case the corresponding author did not respond, a subsequent email was sent and copied to a second author. Where this failed to generate a response, attempts to obtain the data were terminated. 10.1371/journal.pone.0213099.t001 ###### Summary of reviewed studies with non-clinical samples. ![](pone.0213099.t001){#pone.0213099.t001g} Author/s(year) Country Sample characteristics (n; M~age~, SD; % female) Design and mediation test Attachment figure Attachment measures Mediator measures Outcome measures Attachment type Mediation results Quality rating ----------------------------------------------------------------------- --------------------------------------------------------------------------------------------------------------- -------------------------------------------------- ------------------------------ ---------------------------- -------------------------------------------------------------------------------------------------------------------- ----------------------------------------------------- ------------------- ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ---------------- Dakanalis et al. (2016) Italy \[[@pone.0213099.ref011]\] 2055 College students; M~age~ = 18.34, SD = 0.28; 52,2% LO; SEM Bootstrapping Close relationships ASQ 16-item Hypersensitive Narcissism Scale of NPI-40 (Italian version) Dieting and Bulimia subscales of EAT-26 Anxious, Avoidant Vulnerable narcissism fully mediated the effect of attachment anxiety on future bulimic behaviors among women and men. Grandiose narcissism fully mediated the association between attachment avoidance and future dieting behaviors in women and in men. Moderate Boone (2013) Belgium \[[@pone.0213099.ref028]\] 328 Adolescents; M~age~ = 17.1, SD = 1.13; 57% CS; Baron & Kenny steps, Sobel test Mother ECR-R PSP subscale of PSPS; SPP subscale of MPS-H&F Bulimia subscale of EDI-II Avoidant Perfectionism Self-Promotion fully mediated the relationship between avoidant attachment towards father and binge eating. Moderate Bäck (2011) Sweden \[[@pone.0213099.ref042]\] 80 High school students; M~age~ = 18, SD = 0.62; 43,75% CS; Hierarchical regression analysis, Sobel Test Mother AAP Body and weight dissatisfaction through 2 items ChEAT Fearful Body and weight dissatisfaction fully mediated the relationship between secure mother attachment and eating problems. Body and weight dissatisfaction partially mediated the relationship between fearful mother attachment and eating problems. Weak Bamford & Halliwell (2009) UK \[[@pone.0213099.ref043]\] 213 Undergraduate students; M~age~ = 21, SD = 4.1; 100% CS; SEM Close relationships ECRQ-R SCMPS EDI Anxious Social comparison mediated the relationship between insecure attachment and ED. Weak Eggert, Levendosky & Klump (2007) US \[[@pone.0213099.ref046]\] 85 Twins and triplets' community/university; M~age~ = 20.6, SD = 2.7; 100% CS; Hierarchical linear models regressions Romantic partner AAS NEO-PI-R MEBS Anxious Neuroticism fully mediated the relationship between insecure attachment and eating symptoms. Weak Han & Pistole (2014) US \[[@pone.0213099.ref047]\] 381 University students; M~age~ = 25.29, SD = 6.0; 58% CS; SEM Close relationships ECR-S DERS BES Insecure Attachment insecurity and binge eating were associated and mediated by emotion dysregulation. Moderate Kiang & Harter (2006) US \[[@pone.0213099.ref048]\] 146 Undergraduate students; M~age~ = 19.5; 100% CS; SEM Close relationships, Mother ECR Ineffectiveness, perfectionism, interpersonal distrust, interoceptive awareness, and maturity subscales from EDI-2 Drive for thinness and bulimia subscales from EDI-2 Anxious, Avoidant Eating psychological symptoms mediated the relationship between insecure attachment and eating behavioural symptoms. Weak Koskina & Giovazolias (2010) Greece \[[@pone.0213099.ref049]\] 481 Undergraduate students: Male: M~age~ = 21.92, SD = 3.75; Female: M~age~ = 20.75, SD = 3.50; 79.2% CS; Baron & Kenny steps, Sobel test Romantic partner ECR-SR BSQ-34 EAT-26 Anxious Body dissatisfaction fully mediated the relationship between insecure anxious attachment and eating symptomatology (dietary symptoms and bulimia) among women. Body dissatisfaction mediated the relation between anxious attachment and dietary among men. Weak McDermott et al. (2015) US \[[@pone.0213099.ref050]\] 2644 University students; M~age~ = 22.5, SD = 5.26; 46% CS; SEM Bootstrapping Romantic partner ECR-S ATHS CCAPS-62 Anxious, Avoidant Hope mediated the associations between adult attachment dimensions (anxiety and avoidance) and eating problems. Moderate Pepping et al. (2015) Australia \[[@pone.0213099.ref051]\] [Study 1]{.ul}: 144 Undergraduate students; M~age~ = 20.89, SD = 4.80; 100% CS; Bootstrapping Close relationships ECR-R FFMQ EDI-3 Anxious, Avoidant Lower mindfulness mediated the associations of both attachment anxiety and avoidance with increased eating pathology. Weak Schembri & Evans (2008) Australia \[[@pone.0213099.ref052]\] 225 Participants community/university; M~age~ = 30.24, SD = 10.44; 100% CS; Hierarchical Multiple Regression, Sobel Test Romantic partner Anxiety dimension from ECR CESD, RSE BULIT-R Anxious General psychopathology (combined scores of depression and self-esteem) partially mediated the relationship between anxious attachment and bulimic symptoms. Weak Shanmugan, Jowett & Meyer (2012) UK \[[@pone.0213099.ref053]\] 411 British athletes; M~age~ = 20.95, SD = 3.67; 61,3% CS, Bootstrapping Mother, Father, Peers, Coach ECR FMPS, DAS, RSES, Subscale of depression of SCL-90 EDEQ Anxious, Avoidant Self-esteem, depression, and self-critical perfectionism mediated between Insecure attachment styles (anxious and avoidant) and athletes' eating pathology. Moderate Ty & Francis (2013) Australia \[[@pone.0213099.ref054]\] 247 Participants community; M~age~ = 24.51, SD = 4.05; 100% CS, Bootstrapping Close relationships ECR-RS SCMPS, PACS, DERS EAT-26 Anxious, Avoidant Social comparison and emotion dysregulation mediated between insecure attachment and disordered eating. Weak Van Durme, Braet & Goossens (2015) Belgium \[[@pone.0213099.ref055]\] 952 Adolescents primary/secondary schools; M~age~ = 12.9, SD = 1.06; 54,6% CS; Bootstrapping Mother ECR-R-C FEEL-KJ ChEDE-Q Anxious, Avoidant Maladaptive emotion regulation partially mediated the relationships between both attachment anxiety and attachment avoidance towards mother and restraint and eating pathology concerns. Moderate Note. CS = Cross-sectional; LO = Longitudinal; SEM = Structural Equation Modelling; AAP = Adult Attachment Protypes; ChEAT = Children's Eating Attitudes Test; ECRQ-R = Experiences in close relationships questionnaire-Revised; SCMPS = Social Comparisons to models and peers scale; EDI = Eating Disorder Inventory; ECR-R = Experiences in Close Relationships Scale-Revised; PSPS = Perfectionistic Self-presentation Scale; MPS-H&F = Multidimensional Perfectionism by Hewitt and Flett; EDI-II = Eating Disorders Inventory-Two; ASQ = Attachment Style Questionnaire; NPI = Narcissistic Personality Inventory; EAT-26 = Eating Attitude Test-26; NEO-PI-R = NEO Personality Inventory-Revised; MEBS = Minnesota Eating Behavior Survey; DERS = Difficulties in Emotion Regulation Scale; BES = Binge Eating Scale; ECR = Experiences in Close Relationships Scale; EDI-2 = Eating Disorders Inventory-Two; ECR-SR = Experiences in Close Relationships Scale-Revised; BSQ-34 = Body Shape Questionnaire-24; ATHS = Adult Trait Hope Scale; CCAPS-26 = Counseling Center Assessment of Psychological Symptoms-62; FFMQ = The Five Facet Mindfulness Questionnaire; EDI-3 = Eating Disorders Inventory-Three; CESD = Centre for Epidemiological Studies---Depression Scale; RSE = Rosenberg Self-Esteem Scale; BULIT-R = Bulimia Test---Revised; ECR-RS = Relationships Structures; FMPS = Frost Multidimensional Perfectionism Scale; DAS = Dysfunctional Attitude Scale; RSES = Rosenberg's Self-Esteem Scale; SCL-90-R = Symptom Checklist 90-Revised; PACS = Physical appearance comparison scale; ECR-R-C = The experiences of Close Relationships-Revised-Child Version; FEEL-KJ = The questionnaire to assess children's and adolescents'ER strategies; ChEDE-Q = The children's eating disorder examination-questionnaire. 10.1371/journal.pone.0213099.t002 ###### Summary of reviewed studies with clinical samples. ![](pone.0213099.t002){#pone.0213099.t002g} Author/s(year) Country Sample characteristics (n; M~age~, SD; % female) Design and mediation test Attachment figure Attachment measures Mediator measures Outcome measures Attachment type Mediation results Quality rating ---------------------------------------------------------------------- ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ ------------------------------------------------------ --------------------- --------------------- ------------------------------------------------------------------------------------------- ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ -------------------------------------------------------------------------- ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ---------------- Tasca et al. (2009) Canada \[[@pone.0213099.ref044]\] 310 Patients with ED (AN = 74, BN = 138, EDNOS = 98); BMI = 21.88 (6.20); M~age~ = 26.31, SD = 8.76; 100% CS; SEM, Bootstrapping Close relationships ECR DSI-R, PAI EDI Anxious Emotional reactivity mediated the relationship between attachment anxiety contributed and both depressive symptoms and ED symptoms. Emotional deactivation did not mediate the relationship between avoidance attachment and ED symptoms. Moderate Tasca et al. (2006) Canada \[[@pone.0213099.ref045]\] 268 Patients with ED (ANR = 30 M~age~ = 26.4, SD = 10.4; ANB = 43, M~age~ = 29.8, SD = 10.8; BN = 57, M~age~ = 29, SD = 8.0; BED = 115, M~age~ = 42.3, SD = 10.8; EDNOS = 23 M~age~ = 26.2, SD = 8.6); 100% CS; SEM Close relationships ASQ Body dissatisfaction scale-EDI, Body Esteem-Appearance, Body esteem-Weight scales- BESAA. Pressure to diet by family of origin, pressure to diet by current relationships, pressure to diet by authority subscales from DSED-R, Drive for thinness scale-EDI, Restraint scale-EDEQ Anxious, Avoidant Body dissatisfaction mediated the relationship between attachment insecurity style and restrained eating Weak Pepping et al. (2015) Australia \[[@pone.0213099.ref051]\] [Study 2]{.ul}: 55 Patients with ED (BN = 11, BED = 18, EDNOS = 26); M~age~ = 39, SD = 12.66; 100% CS, Bootstrapping Close relationships ECR-R FFMQ EDI-3 Anxious, Avoidant Lower mindfulness mediated the associations of both attachment anxiety and avoidance with increased eating pathology Weak Dakanalis et al. (2014) Italy \[[@pone.0213099.ref056]\] 403 Patients with ED (AN = 101, BN = 167, EDNOS = 135); BMI = 17 (0.9); M~age~ = 25.33, SD = 6.11; 100% CS; SEM, Bootstrapping Close relationships ASQ MPS EDI-2 Anxious, Avoidant Maladaptive perfectionism mediated between both insecure attachment patterns and ED symptoms. It also interacted with insecure attachment to predict higher levels of ED symptoms (moderation). Moderate De Paoli et al. (2017b) Australia \[[@pone.0213099.ref057]\] 744 Participants; M~age~ = 22.53, SD = 7.60; [Clinical group]{.ul}: 122 Patients with ED (AN-R = 56, AN-C = 17, BN = 17, BED = 10, OSFED = 22); BMI = 20.98 (4.59); M~age~ = 25.16, SD = 7.60; 98% [Control group:]{.ul} 662 Participants community/university; M~age~ = 22.01, SD = 8.63; 79% CS/Case-control; SEM Close relationships ECR-R RSQ, Appearance RS-Scale, SCRS EDI-3 Avoidant, Anxious For the ED group, appearance-based RS and social rank were significant mediators of the relationship between insecure attachment and disordered eating. For the controls, interpersonal RS, appearance-based RS and social rank were mediators of the relationship between insecure attachment and disordered eating. Moderate De Paoli et al. (2017a) Australia \[[@pone.0213099.ref058]\] 616 Participants; M~age~ = 22.18, SD = 7.77; [Clinical group:]{.ul} 108 Patients with ED (AN-R = 50, AN-BP = 15, BN = 17, OSFED = 19); BMI = 21.74 (4.23); M~age~ = 25.45, SD = 7.65; 100%; [Control group:]{.ul} 508 Participants community/university; M~age~ = 21.49, SD = 7.63; 100% CS/Case-control; SEM Close relationships ECR-R RSQ, Appearance RS-Scale, SCRS EDE-Q Anxious, Avoidant Emotional deprivation, fear of abandonment, interpersonal RS, and appearance‐based RS mediated between anxious attachment and disordered eating. Moderate Jakovina et al. (2018) Croatia \[[@pone.0213099.ref059]\] 100 Participants; M~age~ = 20.40, SD = 3.26; 100%; Clinical Group BN = 50; Control group = 50 CS; Multiple regression, Sobel test Close person ECR-R DERS (Difficulties in Emotion Regulation Scale) EDI-2 Anxiety Emotion regulation fully mediated between anxious attachment and BN symptoms. Moderate Monteleone et al. (2017) Italy \[[@pone.0213099.ref060]\] 230 Participants; [Clinical group:]{.ul}113 Patients with ED (AN = 71; M~age~ = 24.7, SD = 7.8; BN = 52); BMI = 18.5--25.0; M~age~ = 27.8, SD = 9.4;100%. [Control group:]{.ul} 117 University students; M~age~ = 24.7, SD = 3.1; 100% CS/ Case-control; PROCESS, Sobel test, Bootstrapping Close relationships ECR-R IDEA EDI-II Avoidant Embodiment mediated the relationship between avoidant attachment style and ED symptomatology. Moderate Monteleone et al. (2018) Italy \[[@pone.0213099.ref061]\] 123 Participants; Clinical Group = 78, AN R = 38, AN BP = 10; M~age~ = 25.15, SD = 9; BN = 30; M~age~ = 27, SD = 9.13; Control group = 45, M~age~ = 26.25, SD = 1.95; 100% CS; PROCESS, Bootstrapping Close person ASQ BIS-BAS EDI-2 Anxiety Sensitivity to punishment fully mediated the association between anxious attachment style and ED symptoms (drive to thinness and body dissatisfaction). Moderate Münch, Hunger & Schweitzer (2016) Germany \[[@pone.0213099.ref062]\] 253 Participants; M~age~ = 25.72, SD = 8.73; [Clinical group]{.ul}:106 Participants with ED (Self-reported having ED: AN = 45, BN = 29, Other ED = 12; cut-off \< 20); M~age~ = 24.74, SD = 7.71; 100% [Control group]{.ul}: 147 Participants; M~age~ = 25.72, SD = 8.73; 100% CS/ Case-control; Bootstrapping Close relationships AAS B5T, EXIS EDE-Q, SEED Insecure Personality variables (neuroticism and introversion) and family dysfunction were found to partial mediate the relationship between insecure attachment and eating disorder. Weak Redondo & Luyten (2018) Spain \[[@pone.0213099.ref063]\] 361 Participants; Clinical Group AN = 38; M~age~ = 21.9, SD = 5.30; Control group = 327; M~age~ = 19.1, SD = 1.94; 100% CS; SEM Parents CaMir MAAS EAT-26 Preocupationn, Parental interference, Self-Sufficiency, Childhood trauma Impairments in cognitive attention to internal mental states mediated the relationship between insecure attachment styles and ED symptoms (Dieting, Bulimia and Food preoccupation, Oral control). Moderate Note. CS = Cross-sectional; LO = Longitudinal; SEM = Structural Equation Modelling; AN = Anorexia Nervosa; BN = Bulimia Nervosa; BED = Binge Eating Disorder; EDNOS = Eating Disorder Non Otherwise Specified; ASQ = Attachment Style Questionnaire; MPS = Multidimensional Perfectionism Scale; EDI-2 = Eating Disorders Inventory-Two; ECR-R = Experiences in Close Relationships Scale-Revised; RSQ = Rejection Sensitivity Questionnaire; RS = Rejection Sensitivity; SCRS = Social Comparison Rating Scale; EDI-3 = Eating Disorder Inventory-3; EDE-Q = Eating Disorder Examination Questionnaire; DERS = Difficulties in Emotion Regulation Scale; IDEA = Identity and Eating Disorders; BIS-BAS = Behavioral Inhibition System- Behavioral Activation System Scale; B5T = Big-Five Personality Test; EXIS = Experiences in Personal Social Systems Questionnaire; EDEQ = Eating Disorder Examination Questionnaire; SEED = Short evaluation of Eating Disorders; FFMQ = The Five Facet Mindfulness Questionnaire; CaMir = Cartes, Modèles Individuels de Relation; MAAS = Mindfulness Attention and Awareness Scale; BESAA = Body Esteem Scale for Adolescents and Adults; DSED-R = Diagnostic Survey of Eating Disorders-Revised; DSI-R = Differentiation of self-inventory---revised; PAI = Personality assessment inventory; EDI = Eating Disorder Inventory. Data synthesis and analysis {#sec010} --------------------------- Meta-analysis was conducted for a subset of included mediation models using the software Comprehensive Meta-Analysis (CMA). Initial meta-analyses were conducted in order to: 1) calculate the overall effect size of the mediators among all studies, 2) compare if the effect sizes differed according to the attachment type, and 3) investigate if the magnitude of the effect sizes of the mediators differed by gender. Before pooling, we categorized the data by mediators. We used β (standardized regression coefficients) or, failing that, r (Pearson correlation coefficient) \[[@pone.0213099.ref064]\], and sample sizes to calculate a pooled effect size for the indirect (a\b) and total effects (path c) \[[@pone.0213099.ref065]\]. In cases where studies presented their results under the form of unstandardized regression coefficient, we calculated β* \[β = B\(S~x~/S~y~)\] \[[@pone.0213099.ref066]\]. To provide a summary of each mediation model, we calculated the mediation ratio* \[[@pone.0213099.ref067]\] of the pooled indirect effect and the pooled total effect \[(P~M~ = (a\b/c)\] \[[@pone.0213099.ref068]\]. The I^2^ statistic was used to assess the heterogeneity. We present both fixed-effects and random-effects pooled estimates but use the latter when heterogeneity was present. We assessed publication bias visually through funnel plots ([Fig 2](#pone.0213099.g002){ref-type="fig"}) and formal testing using Egger's test \[[@pone.0213099.ref069]\]. We also performed sensitivity analyses, recalculating the pooled estimates under extreme conditions. ![Funnel plots of correlations versus variance of correlations for total effect (path c) and indirect effect (path a\b).\ Left hand side: Funnel plot for the total effect (path c). Right hand side: Funnel plot for the indirect effect (path a\b). In both charts, Egger's test p-value shows no publication bias (p \> .05).](pone.0213099.g002){#pone.0213099.g002} Assessment of the quality of the studies {#sec011} ---------------------------------------- Eligible papers were evaluated for methodological quality with an adapted version for the present study of the critical appraisal tool developed by Lee et al. \[[@pone.0213099.ref038]\]. Further, four items were added in view of standard guidelines \[[@pone.0213099.ref070],[@pone.0213099.ref071]\]. As a result, a checklist of nine items was obtained ([S1 Appendix](#pone.0213099.s001){ref-type="supplementary-material"}). The items included were as follows: clear description of objectives; appropriate design; representative sample; psychometric characteristics of the mediator and outcome variables reported; ascertain whether changes in the mediating variable preceded changes in the outcome variable; ascertain whether changes in the predictor variable preceded changes in the mediator variable; findings clearly described; and control for confounds. Each study was independently rated providing a score of 1 (yes) or 0 (no) to the 9 items. Studies were categorized into weak (scoring 0--4), moderate (scoring 5--7), and strong (scoring 8--9) based on these criteria. Disagreements between reviewers were resolved by discussion. Furthermore, we carried out a pooled analysis comparing low quality studies (scores \< 5) with moderate-high quality studies (scores = \> 5). Results {#sec012} ======= Main characteristics of included studies in the review {#sec013} ------------------------------------------------------ [Fig 1](#pone.0213099.g001){ref-type="fig"} summarizes the results of different stages of the systematic literature search. Initially, a total of 1655 records were selected as eligible to be screened by title and abstract, of which 110 were retrieved as potential relevant full-text and screened to determine eligibility. Among them, 86 did not meet the inclusion criteria and were excluded. Finally, 24 articles met inclusion criteria and were included for review, of them 21 were eligible for the meta-analysis. As already noted, Tables [1](#pone.0213099.t001){ref-type="table"} and [2](#pone.0213099.t002){ref-type="table"} show the characteristics of each study. Regarding the design of the included studies, most of them adopted cross-sectional designs (n = 23) and only one used a longitudinal design \[[@pone.0213099.ref011]\]. Included studies were conducted in eleven different countries. In reference to the characteristics of the sample, 14 studies used a community sample reported on adolescents (n = 2), university students (n = 8), and young adults (n = 4). Eight studies included both genders and six employed only women. Sample sizes ranged from 80 to 2644 participants and the mean age of participants across studies ranged from 12.9 to 39 years. Eleven studies used clinical samples, including Pepping's et al. \[[@pone.0213099.ref051]\] work referred to patients and three studies that combined samples of patients with EDs and healthy participants when performing the mediating analyses \[[@pone.0213099.ref059],[@pone.0213099.ref061],[@pone.0213099.ref063]\]. Three studies compared clinical and healthy samples. Five studies used exclusively samples with ED patients. Participants with ED were diagnosed using DSM-5 (n = 4), DSM-IV-TR (n = 3), or DSM-IV (n = 1). Two studies \[[@pone.0213099.ref044],[@pone.0213099.ref059]\] did not report any criteria and one study relied on the self-informed diagnosis of the participant \[[@pone.0213099.ref062]\]. A total of 558 patients with a diagnosis of Anorexia Nervosa (AN), 568 of Bulimia Nervosa (BN), 143 of Binge Eating Disorder (BED) and 335 of Eating Disorder-Not Otherwise Specified (EDNOS) were included in the meta-analysis. Sample sizes ranged from 38 to 403 patients and their mean ages ranged from 21.17 to 39 years. Attachment was assessed using the following self-report measures: The Attachment Style Questionnaire (ASQ) \[[@pone.0213099.ref072]\] (n = 4), a 40-item self-report questionnaire containing five scales: (a) adult secure attachment (via the Confidence scale), b) insecure anxious attachment (via the Need for approval and the Preoccupation with relationships scales), and (c) insecure avoidant attachment (via the Discomfort with closeness and Relationships as secondary scales); Adult Attachment Prototypes (AAP) \[[@pone.0213099.ref073]\] (n = 1), an instrument that assesses four categories of attachment described by Bartholomew and Horowitz \[[@pone.0213099.ref022]\]: secure, preoccupied, dismissing and fearful attachment; Adult Attachment scale (AAS) \[[@pone.0213099.ref074]\] (n = 2), an 18-item measure of attachment that yields scores for three adult attachment styles: secure (i.e., comfortable with closeness and independence in relationships), avoidant (i.e., prefer emotional distance from other people), and resistant (i.e., prefer closeness and worry about being abandoned); Cartes, Modèles Individuels de Relation (CaMir) \[[@pone.0213099.ref075]\] (n = 1), a questionnaire that measures insecure attachment assessing four dimensions (Preoccupation, Parental Interference, Self-Sufficiency, and Childhood Trauma); and Experiences in Close Relationships (ECR) \[[@pone.0213099.ref076]\] (n = 16) (including original version, revised versions or version adapted to children) which contains 36 items distributed in two subscales: (a) attachment related anxiety (i.e., the extent to which people are insecure vs. secure about the availability and responsiveness of close person) and (b) attachment related avoidance (i.e., the extent to which people are uncomfortable being close to others vs. secure depending on others). Furthermore, as attachment figure, studies assessed mother (n = 2); mother and father (n = 3); romantic partner (n = 3); parents, peers and romantic partner (n = 1) and the other studies referred to other close relationships (n = 15). The main mediators explored in the reviewed literature were the following: emotional dysregulation (n = 5), body dissatisfaction (n = 4), social comparison (n = 3), perfectionism (n = 3), depressive symptoms (n = 2), mindfulness (n = 2) and neuroticism (n = 2). Additionally, other personality variables such as extraversion (n = 1) and narcissism (n = 1) and other mechanisms such as hope (n = 1), fear of abandonment (n = 1), family functioning (n = 1), appearance-based rejection sensitivity (n = 1), sensitivity to punishment (n = 1) and specific psychological ED traits (i.e., ineffectiveness, perfectionism, interpersonal distrust, interoceptive awareness, and maturity subscales taken from EDI-2) (n = 1) were tested as mediators; however, results regarding these variables were inconclusive due to the reduced sample size. The main ED symptoms involved as the outcome of the mediation models included in this study were the following: bulimic symptoms (n = 7), diet (n = 5), body dissatisfaction (n = 3), binge eating (n = 1), interoceptive awareness EDI-2 (n = 1), impulsivity EDI-2 (n = 1), drive for thinness EDI-2 (n = 4), eating problems (n = 3), disordered eating (n = 2), ED symptoms (n = 5), eating pathology (n = 1), and eating behavioral problems (n = 1). The methodological quality of the 24 retrieved studies ranked from 3 (weak) to 8 (strong) (see [Table 3](#pone.0213099.t003){ref-type="table"} for individual study quality ratings). The pooled estimate for the indirect effect of mediating variables was 62% and 53% for low quality studies and for moderate-high quality studies, respectively. In consequence, no significant differences in our results were found regarding quality. 10.1371/journal.pone.0213099.t003 ###### Quality assessment of the included studies. ![](pone.0213099.t003){#pone.0213099.t003g} Aim clear Design appropriate to aim Sample representative Psychometric characteristics Acceptable methods of data analysis Changes in M preceded changes in Y Changes in X preceded changes in M Clear findings Control confounding factors Final Rating ------------------------------------------------ ----------- --------------------------- ----------------------- ------------------------------ ------------------------------------- ------------------------------------ ------------------------------------ ---------------- ----------------------------- -------------- Dakanalis et al. \[[@pone.0213099.ref011]\] 1 1 0 1 1 1 1 1 1 8* Boone \[[@pone.0213099.ref028]\] 1 1 0 1 1 0 0 1 1 6 Bäck \[[@pone.0213099.ref042]\] 1 1 0 0 0 0 0 0 1 3 Bamford & Halliwell \[[@pone.0213099.ref043]\] 1 1 0 1 1 0 0 1 0 5 Tasca et al. \[[@pone.0213099.ref044]\] 1 1 0 1 1 0 0 1 1 6 Tasca et al. \[[@pone.0213099.ref045]\] 1 1 0 1 1 0 0 0 0 4 Eggert et al. \[[@pone.0213099.ref046]\] 1 1 0 1 0 0 0 1 0 4 Han et al. \[[@pone.0213099.ref047]\] 1 1 0 1 1 0 0 1 1 6 Kiang et al. \[[@pone.0213099.ref048]\] 1 1 0 1 1 0 0 1 0 5 Koskina et al. \[[@pone.0213099.ref049]\] 1 1 0 1 0 0 0 1 1 5 McDermott et al. \[[@pone.0213099.ref050]\] 1 1 1 1 1 0 0 1 0 6 Pepping et al. \[[@pone.0213099.ref051]\] 1 1 0 1 1 0 0 1 0 5 Schembri et al. \[[@pone.0213099.ref052]\] 1 1 1 1 0 0 0 1 0 5 Shanmugan et al. \[[@pone.0213099.ref053]\] 1 1 1 1 1 0 0 1 1 7 Ty et al. \[[@pone.0213099.ref054]\] 1 1 0 1 1 0 0 1 0 5 Van Durme et al. \[[@pone.0213099.ref055]\] 1 1 1 1 1 0 0 1 1 7 Dakanalis et al. \[[@pone.0213099.ref056]\] 1 1 0 1 1 0 0 1 1 6 De Paoli et al. \[[@pone.0213099.ref057]\] 1 1 0 1 1 0 0 1 1 6 De Paoli et al. \[[@pone.0213099.ref058]\] 1 1 0 1 1 0 0 1 1 6 Jakovina et al. \[[@pone.0213099.ref059]\] 1 1 0 1 0 0 0 1 1 5 Monteleone et al. \[[@pone.0213099.ref060]\] 1 1 1 1 1 0 0 1 0 6 Monteleone et al. \[[@pone.0213099.ref061]\] 1 1 0 1 1 0 0 1 0 5 Münch et al. \[[@pone.0213099.ref062]\] 1 0 0 1 1 0 0 1 0 3 Redondo & Luyten \[[@pone.0213099.ref063]\] 1 1 0 1 1 0 0 1 0 5 Meta-analysis {#sec014} ------------- The pooled correlation coefficients for path a, path b, total effect and indirect effect, with their CIs, the I^2^ statistic and effect sizes of each mediation model (mediation ratio) are presented in [Table 4](#pone.0213099.t004){ref-type="table"}. 10.1371/journal.pone.0213099.t004 ###### Random effects pooled correlation coefficients of path a, path b, indirect effect and total effect; heterogeneity and mediation ratio. ![](pone.0213099.t004){#pone.0213099.t004g} -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- N° of models Path a\ I^2^ Path b\ I^2^ Path c\ I^2^ Path a\b\ I^2^ \\|a\b/c\\| (95% CI) (95% CI) (95%CI) (95%CI) -------------------------- -------------- ----------------------- ---------- ----------------------- ---------- ----------------------- ---------- ----------------------- ---------- ------------ Total 21 0.32 (0.13--0.49) 0.98 0.34 (0.19--0.47) 0.97 0.28 (0.20--0.37) 0.92 0.17 (0.10--0.23) 0.85 0.61 Clinical sample 6 -0.08 (-0.52--0.40) 0.99 0.04 (-0.41--0.34) 0.98 0.10 (-0.20--0.38) 0.96 0.01 (-0.18--0.20) 0.90 0.10 Non-clinical sample 14 0.45 (0.28--0.59) 0.97 0.45 (0.34--0.55) 0.95 0.34 (0.27--0.40) 0.80 0.20 (0.14--0.26) 0.75 0.59 Anxious 15 0.34 (0.12--0.53) 0.98 0.34 (0.15--0.50) 0.98 0.31 (0.21--0.40) 0.92 0.17 (0.10--0.24) 0.84 0.55 Avoidant 12 0.11 (-0.06--0.27) 0.96 0.20 (0.02--0.37) 0.97 0.22 (0.14--0.30) 0.85 0.09 (0.03--0.15) 0.70 0.41 High quality 9 0.20 (-0.12--0.48) 0.99 0.22 (0.01--0.41) 0.93 0.15 (-0.01--0.30) 0.95 0.08 (-0.04--0.20) 0.92 0.53 Low quality 12 0.41 (0.16--0.60) 0.98 0.42 (0.20--0.60) 0.97 0.37 (0.31--0.43) 0.65 0.23 (0.17--0.28) 0.51 0.62 Females only 15 0.34 (0.08--0.55) 0.98 0.38 (0.17--0.56) 0.98 0.33 (0.22--0.44) 0.93 0.19 (0.10--0.27) 0.83 0.58 Dysfunctional ER 5 0.33 (-0.24--0.73) 0.99 0.31 (-0.01--0.57) 0.98 0.21 (-0.06--0.45) 0.97 0.15 (-0.06--0.35) 0.95 0.71 Clinical 1 -0.64 (-0.70 − -0.57) \-- -0.37 (-0.46 − -0.27) \-- -0.35 (-0.44 − -0.25) \-- -0.24 (-0.34 − -0.13) \-- 0.69 Non clinical 3 0.52 (0.001--0.81) 0.99 0.42 (0.24--0.57) 0.93 0.30 (0.16--0.43) 0.86 0.21 (0.01--0.40) 0.93 0.70 Depressive symptoms 2 0.49 (0.34--0.61) 0.80 0.52 (0.41--0.62) 0.70 0.35 (0.20--0.48) 0.73 0.25 (0.12--0.57) 0.64 0.71 Clinical 0 \-- \-- \-- \-- \-- \-- \-- \-- Non clinical 2 0.49 (0.34--0.61) 0.80 0.52 (0.41--0.62) 0.70 0.35 (0.20--0.48) 0.73 0.25 (0.12--0.57) 0.64 0.71 Body dissatisfaction 4 0.35 (0.25--0.44) 0.42 0.53 (0.26--0.72) 0.94 0.31 (0.21--0.41) 0.46 0.18 (0.05--0.30) 0.62 0.58 Clinical 2 0.28 (0.19--0.36) 0 0.34 (0.10--0.53) 0.80 0.31 (0.22--0.40) 0 0.08 (-0.02--0.18) 0 0.26 Non clinical 2 0.43 (0.34--0.52) 0 0.67 (0.60--0.72) 0 0.39 (0.001--0.68) 0.81 0.28 (0.18--0.38) 0 0.72 Neuroticism 2 0.83 (0.10--0.98) 0.99 0.43 (0.30--0.55) 0.43 0.52 (0.44--0.59) 0 0.28 (0.18--0.38) 0 0.54 Clinical 0 \-- \-- \-- \-- \-- \-- \-- \-- Non clinical 2 0.83 (0.10--0.98) 0.99 0.43 (0.30--0.55) 0.43 0.52 (0.44--0.59) 0 0.28 (0.18--0.38) 0 0.54 Perfectionism 3 0.35 (0.15--0.53) 0.92 0.38 (0.28--0.46) 0.71 0.27 (0.14--0.39) 0.81 0.14 (0.03--0.25) 0.72 0.52 Clinical 1 0.51 (0.43--0.58) \-- 0.46 (0.38--0.53) \-- 0.37 (0.28--0.45) \-- 0.24 (0.15--0.33) \-- 0.65 Non clinical 2 0.26 (0.08--0.43) 0.85 0.33 (0.26--0.39) 0 0.21 (0.07--0.35) 0.74 0.09 (0.02--0.16) 0 0.43 Mindfulness 2 -0.37 (-0.45--0.29) 0 -0.34 (-0.42--0.25) 0 0.27 (0.18--0.35) 0 0.12 (0.03--0.21) 0 0.44 Clinical 1 -0.33 (-0.55--0.07) \-- -0.46 (-0.64--0.22) \-- 0.42 (0.31--0.52) \-- 0.15 (-0.13--0.40) \-- 0.36 Non clinical 1 -0.40 (-0.53--0.25) \-- -0.32 (-0.46--0.17) \-- 0.37 (0.22--0.50) \-- 0.13 (-0.03--0.29) \-- 0.35 Social comparison 3 0.02 (-0.43--0.45) 0.97 0.27 (-0.47--0.79) 0.99 0.14 (-0.24--0.48) 0.95 0.03 (-0.22--0.28) 0.86 0.21 Clinical 1 -0.49 (-0.61 − -0.34) \-- -0.53 (-0.65 − -0.39) \-- -0.30 (-0.45 − -0.13) \-- -0.26 (-0.42 − -0.09) \-- 0.87 Non clinical 2 0.28 (0.19--0.36) 0 0.61 (0.24--0.83) 0.98 0.35 (0.26--0.42) 0 0.17 (0.07--0.26) 0.16 0.49 -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Note. Path a = association between independent variable and mediator; Path b = association between mediator and dependent variable; Path c = total effect of the independent variable on the dependent variable; a\b* = the indirect effect of the independent variable on the dependent variable controlling the mediator; I^2^ = heterogeneity; \\|a\b/c\\| = mediation ratio, effect size in mediation analysis. ### Primary analyses {#sec015} Overall, 61% of the total effect of insecure attachment on eating disorder symptoms was explained by the indirect effect of the main mediating variables (i.e., maladaptive emotion regulation strategies, depressive symptoms, body dissatisfaction, neuroticism, perfectionism, mindfulness and social comparison). Except for the subgroup of studies of low quality and those subgroups which included only two studies (such as mindfulness and neuroticism), heterogeneity was substantial overall and similarly high after stratification by sample, type of attachment or female sample. No individual study seemed to represent an influential point that increased heterogeneity dramatically. We, therefore, focused on the random effects analyses as recommended by experts and presented the fixed effects results for comparison purposes only ([S3 Table](#pone.0213099.s004){ref-type="supplementary-material"}). Comparing sample types, in non-clinical samples the percentage of the total effect explained by the indirect effect was larger (59%) than in clinical samples (10%). Regarding attachment style, the percentage of the total effect explained by the indirect effect was 55% with anxious attachment and 41% with avoidant attachment. Additionally, the effect size of the mediating variables did not significantly differ by gender since the inclusion of men in the sample yielded similar results (61%) to the studies with female-only samples (58%). ### Subgroup analysis by mediators {#sec016} Maladaptive emotion regulation. Overall, the percentage of the total effect explained by the indirect effect was 71% \[[@pone.0213099.ref044],[@pone.0213099.ref047],[@pone.0213099.ref054],[@pone.0213099.ref055],[@pone.0213099.ref059]\]. The pooled estimates of the indirect effect of maladaptive emotion regulation strategies were significant (70%) in studies with non-clinical population \[[@pone.0213099.ref047],[@pone.0213099.ref054],[@pone.0213099.ref055]\]. The only study conducted with clinical sample found that maladaptive emotion regulation strategies did significantly mediate the relationship between insecure attachment and ED symptoms \[[@pone.0213099.ref044]\]. The percentage of the total effect explained by the indirect effect was 69%. Depressive symptoms. The pooled estimate for the indirect effect of depressive symptoms was significant and large among non-clinical population \[[@pone.0213099.ref052],[@pone.0213099.ref053]\]. The percentage of the total effect explained by the indirect effect was 71%. No study evaluated this model among patients with ED. Body dissatisfaction. Overall, the percentage of the total effect explained by the indirect effect was 58%. The pooled estimates of the indirect effect of body dissatisfaction were significant in studies with non-clinical population (72%) \[[@pone.0213099.ref042],[@pone.0213099.ref049]\]. However, body dissatisfaction did not significantly mediate the relationship between insecure attachment and ED symptoms in two studies with clinical samples \[[@pone.0213099.ref045],[@pone.0213099.ref060]\]; 26% of the total effect that was explained by the indirect effect. Neuroticism. The pooled estimate for the indirect effect of neuroticism was significant among non-clinical population \[[@pone.0213099.ref046],[@pone.0213099.ref062]\]. The 54% of the total effect was explained by its indirect effect. No study evaluated this model among patients with ED. Perfectionism. Overall, the 52% of the total effect was explained by the indirect effect of maladaptive perfectionism. The pooled estimate for the indirect effect of perfectionism was significant in studies with non-clinical sample \[[@pone.0213099.ref028],[@pone.0213099.ref053]\], 43% of the total effect was explained by its indirect effect. The only study using a sample with ED patients found that perfectionism was a significant mediator between insecure attachment and ED symptoms among a sample with ED patients \[[@pone.0213099.ref056]\]. Specifically, the 65% of the total effect was explained by its indirect effect. Mindfulness. Overall, 44% of the total effect was explained by the indirect effect \[[@pone.0213099.ref051],[@pone.0213099.ref063]\]. Among non-clinical samples, 35% of the total effect was explained by its indirect effect \[[@pone.0213099.ref051]\]. Mindfulness was also a significant mediator between insecure attachment and ED symptoms among patients with ED \[[@pone.0213099.ref063]\]. The percentage of the total effect that was explained by the indirect effect was 36%. Social comparison. Overall, the percentage of the total effect that was explained by the indirect effect was 21%. The pooled estimate for the indirect effect of social comparison was significant in studies with non-clinical sample \[[@pone.0213099.ref043],[@pone.0213099.ref054]\]. The 49% of the total effect was explained by its indirect effect. The only study conducted with ED patients found that social comparison was a significant mediator between insecure attachment and ED symptoms \[[@pone.0213099.ref057]\]. The percentage of the total effect that was explained by the indirect effect was 87%. Additional mediators. Some studies reported results on other mediators between insecure attachment style and ED symptoms. The number of studies was too low (less than 2) to be included in a meta-analysis. Therefore, these results are displayed in [S4 Table](#pone.0213099.s005){ref-type="supplementary-material"}. Only one longitudinal study identified narcissism* as mediator (explaining 63% of eating disorder symptoms) among a large mixed sample \[[@pone.0213099.ref011]\]. Extraversion and family functioning were found to mediate between insecure attachment and eating symptoms in women with ED, the total effect explained by the indirect effect was 43% and 66% respectively \[[@pone.0213099.ref062]\]. Furthermore, the proportion of the total effect that was explained by the indirect effect of other mediating variables such as hope and specific psychological ED traits were 21% and 37% in non-clinical mixed and female samples \[[@pone.0213099.ref048],[@pone.0213099.ref050]\]. Finally, appearance based rejection sensitivity explained 89% of the symptoms of patients with ED; sensitivity to punishment and fear of abandonment explained 60% and 48%, respectively, of the ED symptoms in both clinical and non-clinical female groups \[[@pone.0213099.ref057],[@pone.0213099.ref058],[@pone.0213099.ref061]\]. ### Publication bias {#sec017} For the total effect (path c), the Egger's test yielded a P value of 0.36. Further, the Trim and Fill method suggested that seven studies might be missing. Without these seven potential studies, the pooled r was 0.28 (95%CI 0.20--0.37). Adding the seven suggested studies, the pooled r was 0.20 (95%CI 0.11--0.28). Similarly, for the indirect effect (path a\b), there was no sign of publication bias since the Egger's test yielded a P* value of .31. The Trim and Fill method suggested adding four studies. Without these four potential studies, the pooled r was 0.17 (95%CI 0.10--0.23). With the four added studies, the pooled r was 0.11 (95%CI 0.04--0.18). These analyses suggest that the observed effects are not meaningfully modified by potential publication bias. ### Sensitivity analysis {#sec018} To further evaluate the possibility that our results could be due to publication bias, we recalculated our pooled estimates under the following extreme assumptions: (1) published studies are only half of the studies identifying mediating variables between insecure attachment and ED symptoms, (2) all unpublished studies found an r of 0, (3) the unpublished studies have a sample size that is the same as the sample average of the published studies. Under these extreme assumptions, the pooled r for path c was still significant \[0.14 (95%CI 0.08--0.20)\]. Similarly, the pooled r for path a\b* showed significance \[0.08 (95%CI 0.04--0.12)\]. As such, these analyses indicate that it is highly unlikely that the observed effects could have been undermined by publication bias. Discussion {#sec019} ========== The aim of this study was to provide a review and meta-analysis of studies investigating the mediators connecting insecure attachment with eating psychopathology at both clinical and sub-clinical level. Our results build on the already existent evidence that insecure attachment and ED symptoms could be explained by the indirect effect of various mechanisms. Consistent with previous reviews \[[@pone.0213099.ref005],[@pone.0213099.ref008]\] and partly with our hypothesis, the mediators with the largest effect size were emotional dysregulation at both clinical and sub-clinical level, and depressive symptoms at sub-clinical level. In addition, body dissatisfaction, neuroticism, perfectionism, mindfulness and social comparison yielded significant impact also, but their effect size ranged from moderate to low. An important contribution of the present study is the meta-analytic evidence of the influence that the aforementioned mediators have, regardless of gender or type of insecure attachment. In fact, current research tends to include male subjects, as insecurely attached men are also a group at risk of presenting disordered eating \[[@pone.0213099.ref077],[@pone.0213099.ref078]\]. Likewise, results of previous reviews did not reveal conclusive data on the existence of an association between specific attachment patterns and ED subtypes \[[@pone.0213099.ref002],[@pone.0213099.ref003]\]. For instance, while some authors \[[@pone.0213099.ref079],[@pone.0213099.ref080]\] have found an association between avoidant attachment and AN, and anxious attachment and BN, others claim that most people with ED have either an avoidant attachment \[[@pone.0213099.ref081]\] or an anxious insecure attachment \[[@pone.0213099.ref082]\]. In light of these findings, further research should perform mediating analyses distinguishing between different diagnoses of ED, as the indirect effect of specific mediating mechanisms might be different regarding the nature of the symptomatology (e.g., emotion dysregulation might have a greater impact on bulimic symptoms). Unexpectedly, we found that effect sizes were larger in general population than in ED patients. These results are in controversy with the broad literature highlighting the higher prevalence of insecure attachment in clinical samples than in non-clinical samples \[[@pone.0213099.ref003]--[@pone.0213099.ref006]\]. This result may be due, at least in part, to the fact that other mediating variables could better explain the relation between insecure attachment and ED symptoms, or even the direct effect of insecure attachment on ED symptoms may be stronger than the indirect effect through mediators in clinical samples of this meta-analysis. In addition, it should be noted the low number of studies with clinical samples. Further research is needed to ascertain this unclear finding. This review underlines dysfunctional emotion regulation as the most robust nexus involved in the relationship between insecure attachment and ED symptoms at both clinical and sub-clinical level. Our findings agree with previous meta-analyses reporting moderate to large effect size of maladaptive emotion regulation strategies, either suppressing or accentuating emotional responses, on ED symptoms \[[@pone.0213099.ref007],[@pone.0213099.ref021]\]. As such, this mechanism emerges as an intermediate pathway that links insecure attachment and ED symptomatology \[[@pone.0213099.ref044],[@pone.0213099.ref047],[@pone.0213099.ref054],[@pone.0213099.ref055],[@pone.0213099.ref059]\]. On the one hand, strategies used to express and to regulate emotions might be determined by the type of attachment \[[@pone.0213099.ref017],[@pone.0213099.ref018],[@pone.0213099.ref083]\] and, on the other hand, ED symptoms could be the manifestation of a difficulty in identifying emotions and an attempt to counteract such discomfort \[[@pone.0213099.ref084],[@pone.0213099.ref085]\]. Consequently, insecurely attached people could either turn to binge eating as a way of getting distracted from adverse emotions \[[@pone.0213099.ref017],[@pone.0213099.ref033]\], or to excessive exercise or dieting to reduce unwanted negative thoughts that very often follow binge eating \[[@pone.0213099.ref047],[@pone.0213099.ref086]\]. As regards to the relative contribution of depressive symptoms, our findings indicate one of the highest effect sizes. Note that these results were based on studies with non-clinical samples, and therefore they are only tentative at best to acknowledge the effect on ED. A broad review \[[@pone.0213099.ref087]\] has concluded that maladaptive cognitive patterns and self-representations arising from negative early attachment experiences place individuals at-risk to develop depressive symptomatology following adverse life events. Related to emotion regulation, previous research suggested that anomalous eating behaviors emanate as a way to self-regulate or escape from negative emotions \[[@pone.0213099.ref033],[@pone.0213099.ref034],[@pone.0213099.ref088]\]. Moreover, depressive symptomatology has been identified as strong predictor of eating problems \[[@pone.0213099.ref012],[@pone.0213099.ref089],[@pone.0213099.ref090]\]. In the present meta-analysis, we found that individuals with insecure attachment think and behave in a manner that favors the development of eating psychopathology through depressive symptoms \[[@pone.0213099.ref052],[@pone.0213099.ref074]\]. These results are in line with the dual pathway model of Stice \[[@pone.0213099.ref091]\] which provided prospective evidence of the mediational role of negative affect along with dieting in the subsequent development of bulimic pathology. Our findings regarding body dissatisfaction suppose a further step that demonstrates the intermediate role of this variable in the relationship between insecure attachment and ED symptomatology \[[@pone.0213099.ref042],[@pone.0213099.ref070]\]. From this perspective, individuals with insecure attachment could be particularly prone to internalize certain aesthetic standards, such as thinness in women or musculature in men, in the pursuit of acceptance and social approval \[[@pone.0213099.ref092],[@pone.0213099.ref093]\]. When these goals are not achieved, body dissatisfaction increases, which in turn triggers a heightened risk for abnormal eating behaviors \[[@pone.0213099.ref092],[@pone.0213099.ref094],[@pone.0213099.ref095]\]. Against expectations, in our meta-analysis, the indirect effect of insecure attachment on ED symptoms through body dissatisfaction yielded not significant effect size among ED samples. It is possible that this result can be explained, at least partially, due to the characteristics of two out of four included studies. Thus, the model tested by Tasca \[[@pone.0213099.ref045]\], specifically designed for patients with BN, was applied to heterogeneous sample of women with ED mostly with AN. In addition, in this study \[[@pone.0213099.ref045]\] the authors simultaneously analyzed the negative affect which could have reduced the effect of body dissatisfaction. Moreover, another included work did not properly assess body dissatisfaction but the lived corporeality, i.e. the difficulty experiencing the body from an inner perspective \[[@pone.0213099.ref060]\]. In view of these considerations and the prominent risk that body dissatisfaction appears to carry to EDs \[[@pone.0213099.ref091],[@pone.0213099.ref096]\], further research should examine its mediational impact in clinical samples. In reference to neuroticism, we identified a significant impact on the development of ED symptoms. Specifically, two studies found that insecurely attached individuals with more neurotic personality characteristics were more likely to display disordered eating symptoms \[[@pone.0213099.ref046],[@pone.0213099.ref062]\]. These findings are consistent with a wide body of literature supporting the link between neuroticism and several clinical and sub-clinical syndromes, among others, eating disorders \[[@pone.0213099.ref097],[@pone.0213099.ref098]\] and, inversely, with the positive association between secure attachment and low neuroticism \[[@pone.0213099.ref099]\]. However, these results should be interpreted with caution, since neuroticism represents an unspecific personality dimension that englobes a variety of facets such as negative affect, affective instability and anxiety, involved in the etiology of diverse mental disorders \[[@pone.0213099.ref097]\]. In the present meta-analysis, maladaptive perfectionism was found to be a significant mediator at both clinical and sub-clinical level. According to the previous literature, insecure attachment strongly predicts the development of maladaptive perfectionism \[[@pone.0213099.ref100]--[@pone.0213099.ref102]\]. Specifically, insecurely attached individuals are likely to be overly self-critical, and therefore, to using strategies, such as maladaptive perfectionism, to counter feelings of worthlessness and hopelessness \[[@pone.0213099.ref092],[@pone.0213099.ref102]\]. In addition, it is well-known the connection between perfectionism and ED symptoms in both clinical and non-clinical samples \[[@pone.0213099.ref056],[@pone.0213099.ref103],[@pone.0213099.ref104]\]. Consequently, people with insecure attachment are prone to seek excellent standards difficult to reach, frequently concerning body shape and weight and its control \[[@pone.0213099.ref019],[@pone.0213099.ref092],[@pone.0213099.ref105]\], which favors the appearance of unhealthy eating behaviors to achieve this unrealistic aims \[[@pone.0213099.ref028],[@pone.0213099.ref053],[@pone.0213099.ref056]\]. Reduced mindfulness capacity (i.e., inability to be fully aware of current experience or present reality) \[[@pone.0213099.ref106]\] was also identified as one of the mediating mechanisms \[[@pone.0213099.ref051],[@pone.0213099.ref063]\]. This result is not surprising as the associations between insecure attachment and mindfulness \[[@pone.0213099.ref106]--[@pone.0213099.ref108]\] and between mindfulness and eating pathology \[[@pone.0213099.ref109],[@pone.0213099.ref110]\] have been previously established. Mindfulness capacity in insecurely attached individuals might be indeed compromised as they tend to engage in cognitive and emotional processes, such as worrying about a future abandonment (anxious attachment) or refusing to attend to an emotion or need (avoidant attachment), that are contrary to mindful states \[[@pone.0213099.ref108]\]. This is especially relevant for patients with bulimia and binge eating who often struggle detecting and discriminating interoceptive cues (i.e., hunger and satiety versus one's inner feelings) \[[@pone.0213099.ref060]\]. Finally, social comparison was identified as a significant mediator in non-clinical and clinical samples, but presented the lowest effect size; therefore, more research is required to confirm this finding. Insecurely attached people develop dysfunctional beliefs about oneself \[[@pone.0213099.ref019]\], that conducted themselves to excessively compare to others whom they deemed potentially better to assess their self-image, which in turn promote the risk for developing abnormal eating attitudes \[[@pone.0213099.ref043],[@pone.0213099.ref054],[@pone.0213099.ref057]\]. Limitations of the present study {#sec020} ================================ The present study has several limitations worth noting. First, due to the scarce number of studies in relation to some mediators, only a subset of the studies could be included in this meta-analysis. Second, the majority of the findings proved in this meta-analysis were provided by normal population (predominantly younger Caucasian women), thus reducing the possibility for generalization; caution is needed in extrapolating the results to other sociodemographic groups. Third, the inclusion of cross-sectional data in the present meta-analysis did not make it possible to draw definitive conclusions regarding the development of the ED psychopathology and reflects the need for future studies to implement prospective designs. Fourth, some of the included studies \[[@pone.0213099.ref042],[@pone.0213099.ref049],[@pone.0213099.ref052],[@pone.0213099.ref059]\] used exclusively Sobel test to prove the significance of mediation despite the fact that this test has been overcome \[[@pone.0213099.ref065]\]. Fifth, the heterogeneity of effects between studies was high. Nevertheless, as it is claimed by experts, heterogeneity in a meta-analysis should be viewed as expected rather than inevitable and not as a nuisance \[[@pone.0213099.ref111]\]. Therefore, we decided to interpret our results taking random-effects estimates as it might be the most appropriate way to deal with this issue \[[@pone.0213099.ref112]\]. Sixth, the mediation ratio \[[@pone.0213099.ref067]\] was used as a summary of the effect size for each mediator despite the fact that it is a measure that suffers from several limitations \[[@pone.0213099.ref035],[@pone.0213099.ref037]\]. However, as the data included in the present meta-analysis reported larger total effects than the indirect effects and of the same sign, we followed recommendations of its application \[[@pone.0213099.ref035]\]. In addition, it should be noted that so far it is the most widely used measure of effect size for mediation models and a method relatively unaffected by sample size. Finally, most studies relied only on self-reports. Hence, some response biases may have affected the results. Overall, the results of this meta-analysis should be interpreted with caution, and only in the context of the characteristics from included studies. Nevertheless, as far as we know, this study is the first meta-analysis exploring the effect sizes of mediators that connect insecure attachment and eating symptoms in both clinical and sub-clinical samples at any age. Implications for research {#sec021} ========================= Future studies should explore prospectively mediating mechanisms implementing designs with a temporal sequence ascertaining the precedence of the independent variable on the mediator and, by the same token, of the mediator on the dependent variable \[[@pone.0213099.ref038]\]. Because of the possible relationship between the main mediators found in this review, it would be interesting to explore the interplay among them through sequential multiple mediation models and moderated mediation models to understand the contribution of each mediator. Further, future mediation studies should apply powerful statistical techniques such as SEM with bootstrapping in order to strengthen conclusions and reporting the magnitude of the mediated effect \[[@pone.0213099.ref065]\]. Additionally, given the paucity of studies, it will be useful in the future to ascertain more precisely whether the mediational effects of such variables differ by specific diagnoses of ED and also by age distribution. Lastly, the control for confounding variables merits particular attention to rule out possible spurious effects \[[@pone.0213099.ref070]\]. Clinical implications {#sec022} ===================== A consistent finding in the literature is the influence of insecure attachment on the poorer therapeutic outcomes among patients with ED \[[@pone.0213099.ref013],[@pone.0213099.ref113]\]; as insecurely attached patients tend to change or to abandon therapy frequently \[[@pone.0213099.ref045],[@pone.0213099.ref114]\]. As suggested by Tasca and Balfour \[[@pone.0213099.ref005]\], clinicians should assess patient's quality and level of attachment in order to adapt the therapy and to guarantee better therapeutic outcomes. Our meta-analytic results suggest that insecure attachment patterns along with others psychological variables may be important targets of clinical interventions of ED; hence, it is recommended that clinicians include therapeutic strategies focused, not only on the quality of attachment, but also on the mediators that maintain and aggravate eating symptomatology or pose a risk for their possible development \[[@pone.0213099.ref115]\]. Adopting this strategy could improve ED treatment outcomes and reduce drop-out rates \[[@pone.0213099.ref116]\]. For instance, intervening at the level of self-representations by improving confidence and to provide skills to better manage negative emotions and interpersonal problems may decrease the distress and subsequent symptoms of eating disorder such as binge eating, purging or extreme exercise or dieting \[[@pone.0213099.ref013]\]. Additionally, the combination of a cognitive-behavioral treatment with mindfulness techniques could be a new path of treatment that could offer promising results \[[@pone.0213099.ref051],[@pone.0213099.ref110]\], as it has been already tested in patients with major depressive disorder \[[@pone.0213099.ref117]\]. Moreover, given the impact of insecure attachment on the later development of eating pathology, early interventions that decrease the onset of EDs are of critical importance. For instance, providing parents with the skills necessary to enhance their children's capacity for self-regulating when facing challenging situations \[[@pone.0213099.ref087]\]. Also, school-based prevention programs for children and adolescents including modules of psychoeducation addressing, not only eating pathology and its risks, but also management of negative emotions, coping with interpersonal problems, confronting rigid and unrealistic standards and the promotion of a healthy self-image, might be important to consider \[[@pone.0213099.ref118]\]. Conclusions {#sec023} =========== The results obtained in the present meta-analysis extend previous findings by showing that emotion dysregulation, depressive symptoms, body dissatisfaction, neuroticism, perfectionism, mindfulness and social comparison could be essential psychological mechanisms for explaining the pathways through which insecure attachment may increase the vulnerability to eating symptoms. However, since the application of mediation analysis in disordered eating research is still in its early stages, more studies are needed to corroborate our results. Specifically, longitudinal studies are required to clarify the interplay of the mediators between insecure attachment and ED symptoms. Supporting information {#sec024} ====================== ###### Checklist for measuring study quality. (DOCX) ###### Click here for additional data file. ###### PRISMA checklist. (DOC) ###### Click here for additional data file. ###### Detailed extracted and coded data for meta-analysis. (DOCX) ###### Click here for additional data file. ###### Fixed effects pooled correlation coefficients of path a, path b, indirect effect and total effect; heterogeneity and mediation ratio. (DOCX) ###### Click here for additional data file. ###### Meta-analysis results for additional mediators. (DOCX) ###### Click here for additional data file. ###### Forest plot path c and random effects summary. (TIFF) ###### Click here for additional data file. ###### Forest plot path a\b and random effects summary. (TIFF) ###### Click here for additional data file. Dr. Takkouche would like to thank the Regional Ministry of Education, Universities and Vocational Training (Consellería de Educación, Universidades y Formación Profesional) (ED431C 2018/20). Santiago de Compostela, Spain. [^1]: Competing Interests:*The authors have declared that no competing interests exist.	{ "pile_set_name": "PubMed Central" }
Francisco I. Madero Refinery The Francisco I. Madero Refinery is an oil refinery located in Ciudad Madero, Tamaulipas, "founded in 1914 by the company El Águila", is currently owned and operated by Pemex, and is one of six refineries of Mexico. References Category:Oil refineries in Mexico	{ "pile_set_name": "Wikipedia (en)" }
Emotional expression and depth processing of trauma and their relation to long-term survival in patients with HIV/AIDS. This study examined the relationship between emotional expression and depth processing of trauma and long-term survival of patients living with AIDS. A further purpose was to examine the immune, health behavior and psychosocial correlates of emotional disclosure and depth processing. Subjects wrote essays describing their reactions to past traumas; these were scored for emotional expression and depth processing (positive cognitive appraisal change, experiential involvement, self-esteem enhancement and adaptive coping strategies). Two HIV-seropositive groups were recruited for this study; long-term survivors (LTS; n=46) patients who had survived at least 4 years past a Category C (AIDS defining) symptom prior to starting protease inhibitors and an equivalent HIV-seropositive comparison group (ECOMP(LTS); n=89) who had CD4+ cells between 150 and 500, and had no history of Category C symptoms. The groups were equivalent on age, gender, ethnicity, education, employment, income, sexual orientation and route of infection. The group LTS were significantly higher than the ECOMP(LTS) group on emotional expression and depth processing. Depth processing mediated the relationship between emotional expression and long-term survival status. Depth processing was positively related to CD4+ cell number for women. Emotional expression was also significantly related to viral load (negatively) and to CD4+ cell number (positively) for women only. Interestingly, only depth processing (and not emotional expression) was related to medication adherence and to psychosocial variables (perceived stress and social support). Emotional expression and depth processing were related to long-term survival, however, depth processing was the mediator for this relationship and only depth processing was associated with medication adherence, perceived stress and social support. Our results underscore the importance of depth processing (and not just emotional expression) of traumatic experiences for people living with HIV/AIDS.	{ "pile_set_name": "PubMed Abstracts" }
Peterborough Lions RFC Peterborough Lions Rugby Football Club, formerly Westwood RUFC, is an English rugby union team based in Bretton near Peterborough. The club runs one senior team, a youth academy team, an under-16s side and four junior teams. with the first XV currently playing in Midlands Premier following their relegation from National League 2 North at the end of the 2018-19 season. Club honours Midlands 2 East (South) champions: 2011-12 Midlands Division 1 East champions: 2013-14 Midlands Premier v North Premier promotion play-off winner: 2017–18 References External links Official club website Category:English rugby union teams Category:Rugby clubs established in 1944	{ "pile_set_name": "Wikipedia (en)" }
The effect of gallium nitrate on synoviocyte MMP activity. Gallium, a group IIIa metal salt, has been demonstrated to be an effective immunosuppressive agent. Gallium has also been shown to inhibit the production of inflammatory cytokines, such as IL-1beta, produced by macrophage-like cells in vitro. To further characterize the effects of gallium on the inflammatory process, we examined the effects of gallium nitrate on matrix metalloproteinase (MMP) activity utilizing the rabbit synoviocyte cell line HIG-82. HIG-82 cells were incubated with IL-1beta and TPA, with and without increasing concentrations of gallium nitrate. Conditioned medium was collected and assayed for MMP activity using a synthetic substrate and substrate gel zymography. IL-1beta and TPA alone induced MMP activity in HIG-82 cells. A dose-dependent inhibition of IL-1beta and TPA stimulated MMP activity by gallium nitrate at increasing concentrations was observed. This study demonstrates that gallium nitrate can inhibit the activity of MMPs and may be useful as a modulator of inflammation in arthritis.	{ "pile_set_name": "PubMed Abstracts" }
Q: Hyperlink or button does not fire inside repeater item template I have a repeater and inside item template I have a button and an anchor. <asp:Repeater runat="server" ID="rptCategoryList" OnItemDataBound="rptCategoryList_ItemDataBound"> <ItemTemplate> .... <div style="margin-left: 81.6%;"> <span runat="server" id="spnRegister" clientidmode="static" class="register pull-right"> <button class="btn btn-info btn-lg" style="float: ; margin-right: 40px; margin-top: -150px; background-color: #3697EA"> <a href="register.aspx" style="color: white;" target="_self">Register</a> </button> </span> </div> .... </ItemTemplate> when this button is clicked it reloads the same page rather going to register.aspx. I used "view page source" and href is set correctly. I removed the anchore and added a class to button and used jQuery: <button class="btn btn-info btn-lg registerSilver" style="float: ; margin-right: 40px; margin-top: -150px; background-color: #3697EA"> Register </button> $(function () { $('.registerSilver').click(function () {debugger window.location = 'register.aspx'; }); }); still not working, keeps reloading the same page. I even tried to add runat="server" to the hyperlink and set its href in repeater's itemdatabound, no luck. What am I missing here? A: The default behavior of <button> tag triggers form submit (i.e. <form runat="server"> in ASPX page), which probably causing postback to same page instead of redirecting to page URL specified in anchor link. Try setting type="button" attribute explicitly like example below: <button type="button" class="btn btn-info btn-lg" style="float: ; margin-right: 40px; margin-top: -150px; background-color: #3697EA"> <a href="register.aspx" style="color: white;" target="_self">Register</a> </button> Or use preventDefault() function for click event handler in jQuery to prevent default submit action of that button: $('.registerSilver').click(function (e) { e.preventDefault(); debugger; window.location = 'register.aspx'; });	{ "pile_set_name": "StackExchange" }
Fusing Heterogeneous Features From Stacked Sparse Autoencoder for Histopathological Image Analysis. In the analysis of histopathological images, both holistic (e.g., architecture features) and local appearance features demonstrate excellent performance, while their accuracy may vary dramatically when providing different inputs. This motivates us to investigate how to fuse results from these features to enhance the accuracy. Particularly, we employ content-based image retrieval approaches to discover morphologically relevant images for image-guided diagnosis, using holistic and local features, both of which are generated from the cell detection results by a stacked sparse autoencoder. Because of the dramatically different characteristics and representations of these heterogeneous features (i.e., holistic and local), their results may not agree with each other, causing difficulties for traditional fusion methods. In this paper, we employ a graph-based query-specific fusion approach where multiple retrieval results (i.e., rank lists) are integrated and reordered based on a fused graph. The proposed method is capable of combining the strengths of local or holistic features adaptively for different inputs. We evaluate our method on a challenging clinical problem, i.e., histopathological image-guided diagnosis of intraductal breast lesions, and it achieves 91.67% classification accuracy on 120 breast tissue images from 40 patients.	{ "pile_set_name": "PubMed Abstracts" }
Dynamic surface tension studies of mixtures of hydroxypropylmethylcellulose with the double chain cationic surfactants didodecyldimethylammonium bromide and ditetradecyldimethylammonium bromide. Dynamic and equilibrium surface tension experiments were carried out to study the adsorption kinetics of mixtures of the nonionic polymer hydroxypropylmethylcellulose (HPMC) with two double chain cationic surfactants, didodecyldimethylammonium bromide (di-DDAB) and ditetradecyldimethylammonium bromide (di-TDAB). Results are obtained concerning the capacity of the surfactants to lower surface tension, the rate of lowering, the extent of adsorption at the interface, the possibility of changing conformation during and after adsorption, and the interactions between the adsorbed molecules. A time-dependent synergy is observed in most of the mixtures, while in a few cases hindrance effects are observed. The interaction of HPMC with the double chain cationic surfactants resulted in complexes with higher surface activity than the two components alone. Two induction times were observed, the second ones being more significant in the presence of di-TDAB. At concentrations well below the critical micelle concentration (cmc), the critical aggregation concentrations (cac), evidence for clusters is observed.	{ "pile_set_name": "PubMed Abstracts" }
August Dieckmann __NOTOC__ August Hinrich Dieckmann (29 May 1912 – 10 October 1943) was a commander in the Waffen-SS of Nazi Germany during World War II. He was a recipient of the Knight's Cross of the Iron Cross with Oak Leaves and Swords. Awards SS Degen (13 September 1936) Iron Cross (1939) 2nd Class (28 September 1939) & 1st Class (3 June 1940) German Cross in Gold on 28 February 1942 as SS-Sturmbannführer in the I./SS-Regiment "Germania" Knight's Cross of the Iron Cross with Oak Leaves and Swords Knight's Cross on 23 April 1942 as SS-Sturmbannführer and commander of the I./SS-Regiment "Germania" 233rd Oak Leaves on 16 April 1943 as SS-Sturmbannführer and commander of the I./SS-Panzergrenadier-Regiment "Germania" 39th Swords on 10 October 1943 (posthumous) as SS-Obersturmbannführer and commander of SS-Panzergrenadier-Regiment 10 "Westland" References Citations Bibliography Category:1912 births Category:1943 deaths Category:SS-Standartenführer Category:German military personnel killed in World War II Category:Recipients of the Gold German Cross Category:Recipients of the Knight's Cross of the Iron Cross with Oak Leaves and Swords Category:Waffen-SS personnel	{ "pile_set_name": "Wikipedia (en)" }
Q: How to generate user-defined warning messages in VB.NET I would like to generate a user-defined warning message in VB.NET as is done in C# (see below): How to use the #pragma message to generate user-defined warning messages in Visual C++ Is this possible? A: No, Unfortunately this is not possible using VB.NET A: It is not done in C#, you refer to something in C++ However, you can use the attribute <Obsolete("some comment")> for classes, functions, and subs; and this does create a warning. Here the code-version, so use Obsolete. Since you can add any text, you should be able to refine the purpose of the warning.	{ "pile_set_name": "StackExchange" }
Intraplaque hemorrhage in symptomatic intracranial atherosclerotic disease. Studies in patients with extracranial carotid disease have shown that high-resolution magnetic resonance direct thrombus imaging (MRDTI) can reliably identify intraplaque hemorrhage, which may be a better predictor of clinical events than traditional radiographic methods such as percent stenosis. We present the use of high-resolution magnetic resonance imaging for the detection of intraplaque hemorrhage in the intracranial arteries. High-resolution 3 Tesla MRDTI was performed using T1-weighted scans with an inversion pulse to null the signal from blood. Abnormal intraplaque T1 signal compatible with hemorrhage or blood products was defined as equal to or higher than 150% of T1 signal of adjacent muscle. The symptomatic middle cerebral artery demonstrated intraplaque signal higher than 150% of the muscle signal in two central slices, consistent with the imaging characteristics of intraplaque hemorrhage demonstrated in extracranial carotid arteries. High-resolution MRDTI of intracranial atherosclerotic lesions could provide a surrogate marker of plaque activity in vivo and could lead to improvements in risk stratification and treatment of this common disease.	{ "pile_set_name": "PubMed Abstracts" }
Q: Pass json object from android(java) to javascript in Webview I am working on an Android Webview Application.I need to call a function from Javascript and the Java function should return a JSON object.If the there is only one value in my JSON object i could access it from Javascript.But if there is more than one i get the value undefined. ex: In Java method JSONObject ob = new JSONObject(); ob.put("hello","hai"); return String.valueOf(ob); In Javascript data = app.getValue(); obj = JSON.parse(data) console.log(obj.hello); The above code works Fine but, In Java method JSONObject ob = new JSONObject(); ob.put("hello","hai"); ob.put("abc","xyz"); return String.valueOf(ob); In Javascript data = app.getValue(); obj = JSON.parse(data) console.log(obj.hello); <- doesn't work console.log(obj[0].hello); <- doesn't work A: Thanks to @slesh,I finally able to solve the problem I changed from return String.valueOf(ob); to this return obj.toString();	{ "pile_set_name": "StackExchange" }
George W. Holmes Lecture. Deep venous thrombosis and pulmonary embolism: correlative evaluation and therapeutic implications. Deep venous thrombosis and pulmonary embolism are significant causes of morbidity and mortality in the United States; estimates range from 120,000 to 150,000 deaths annually. Although usually symptomatic, deep venous thrombosis can be clinically occult, in part due to incomplete obstruction or in part related to duplication, triplication, and fenestration anomalies, primarily of the superficial femoral or popliteal vein. Additionally, pulmonary emboli caused by deep venous thrombosis may be clinically silent. Because of therapeutic implications, especially indications for insertion of inferior vena caval filters, comprehensive assessments of both the disease process (i.e., deep venous thrombosis) and the complication (i.e., pulmonary emboli) are important. Thus, when a pulmonary embolus is the presenting process, correlative assessment of deep venous thrombosis, even in the absence of symptoms or signs in the lower extremity, may be of therapeutic significance. Conversely, when deep venous thrombosis of the lower extremities involving the popliteal or superficial femoral vein is the presenting process, correlative assessment of the pulmonary circulation, even when no pulmonary symptoms or signs are present, may be of therapeutic significance. Relative to the diagnosis of pulmonary embolism, the roles of assays of D-dimer, ventilation-perfusion lung scans, and segmental occlusion studies of the pulmonary circulation are discussed. Finally, the indications for insertion of inferior vena caval filters above the renal veins are presented and examples are shown.	{ "pile_set_name": "PubMed Abstracts" }
Q: Facing performance problems implementing minimax for a chess game I am trying to implement minimax algorithm for a little chess game. Maybe my premise is wrong and this is not something that should be attempted. Is it? The program works but there is a big performance issue: Depth = 0, 1 or 2 the result is immediate. Depth = 3 the result takes 15 seconds. Depth = 4 - haven't got a result yet. Here is my implementation: private Move findBestMove(Chessboard chessboard, int depth, boolean maximizingPlayer) { if (depth == 0) { return new Move(chessboard.calculateHeuristicValue()); } else { Move bestMove; if (maximizingPlayer) { bestMove = new Move(Integer.MIN_VALUE); for (Move possibleMove : findAllPossibleMoves(chessboard, !(maximizingPlayer ^ whiteTurn))) { Move move = findBestMove( possibleMove.getResultChessboard(), depth - 1, !maximizingPlayer); if (move.getValue() > bestMove.getValue()) { possibleMove.setValue(move.getValue()); bestMove = possibleMove; } } } else { bestMove = new Move(Integer.MAX_VALUE); for (Move possibleMove : findAllPossibleMoves(chessboard, !(maximizingPlayer ^ whiteTurn))) { Move move = findBestMove( possibleMove.getResultChessboard(), depth - 1, !maximizingPlayer); if (move.getValue() < bestMove.getValue()) { possibleMove.setValue(move.getValue()); bestMove = possibleMove; } } } return bestMove; } } Maybe there is a fault in the implementation of the algorithm or in the design of the objects or in their use. I cannot put my finger on it. So, I want to be sure that there is no major problem I overlook before trying to optimize the code or to tweak memory configuration of the program. Note: no experience with memory profiling. A: In chess there are 20 possibilities to make the first move (16 by pawns and 4 by knights). For the sake of simplicity, let's assume that this is also true for the next moves. For depth 1, MinMax considers only that 20 moves. For depth 2, MinMax considers 20 moves and 20 answers to that moves, 400 possible moves, no problem. For depth 3, MinMax considers 20^3 = 8.000 possible moves. Already 15 seconds on your machine. For depth 4, MinMax considers 20^4 = 160.000 possible moves. That will take around 20 times longer than the previous one... Simply the search space becomes too big - it grows exponentially with the input (depth) size. Time complexity is O(20^depth). But, we don't have to search through all the space to find really good moves. Alpha-beta pruning is popular optimization for MinMax. If that's not enough, I would consider switching to totally other algorithm - Monte Carlo Tree Search (with UCT) for example. Moves databases could also help - instead of computing the first moves you can have already prepared (pre-computed) gambits. Famous Deep Blue who beat Kasparov in 1997 used them, you can check what else it used here.	{ "pile_set_name": "StackExchange" }
Q: How to add SOAP interface for Delphi Synapse HTTP Server? I've got a custom HTTP Server created using Delphi 7 and Ararat Synapse which receives HTTP GET from another application with a simple set of variables. For example: http://myserver.com/get?Variable1=adsds&Variable2=asdasdasdsa&Variable3=aasdsadasdsad The application source is similar to this - http://searchco.de/codesearch/view/13374072 Now, my customer needs me provide a SOAP interface. Completely new to SOAP, I did some research and found it to be very complicated. I would like to know what's the easier way to incorporate this interface to my HTTP server. Or should I find ready made SOAP To HTTP Conversion app if there is such a software. Thank you. Note: I'm not the original developer of the HTTP Server. A: You need to write a SOAP server, which not only generates SOAP responses from SOAP requests, but which also provides a WSDL document telling the users what requests they can make. Since your completely new to SOAP here are some 'starter' links: General: SOAP, WDSL, HTTP, XSD? What the? List of publicly available web services (I would start writring a small testapp that consumes SOAP) With Delphi: Developing Web Services with Delphi Web Services Made Easy With Delphi Web services with Delphi The fact that you are using Delphi 7 makes things more difficult, since later versions have better support: Debugging/Testing Win32 SOAP Web Services (D2007). Bob has more SOAP articles For testing both serving and consuming SOAP you should use SoapUI, a great free tool (What is SOAPUI?). Once you are up to the WDSL you should know what types of WSDL exist and the whole namespaces mess... A: There is a Web Service Toolkit for Free Pascal and Delphi which can be used to write SOAP servers. I have not yet used it myself but it is in active development and might be compatible with Synapse. Update: the current version seems to include support for Internet Direct (Indy) and Synapse (HTTP server and TCP server).	{ "pile_set_name": "StackExchange" }
Q: Word frequency in a string without spaces and with special characters? Let's say I have the following string: "hello&^uevfehello!`.<hellohowhowdhAreyou" How would I go about counting the frequency of english words that are substrings of it? In this case I would want a result such as: {'hello': 3, 'how': 2, 'are': 1, 'you': 1} I searched previous question which were similar to this one but I couldn't really find anything that works. A close solution seemed to be using regular expressions, but it didn't work either. It might be because I was implementing it wrong since I'm not familiar with how it actually works. How to find the count of a word in a string? it's the last answer from collections import import re Counter(re.findall(r"[\w']+", text.lower())) I also tried creating a very bad function that iterates through every single possible arrangement of consecutive letters in the string (up to a max of 8 letters or so). The problem with doing that is 1) it's way longer than it should be and 2) it adds extra words. ex: if "hello" was in the string, "hell" would also be found. I'm not very familiar with regex which is probably the right way to do this. A: d, w = "hello&^uevfehello!`.<hellohow*howdhAreyou", ["hello","how","are","you"] import re, collections pattern = re.compile("\|".join(w), flags = re.IGNORECASE) print collections.Counter(pattern.findall(d)) Output Counter({'hello': 3, 'how': 2, 'you': 1, 'Are': 1})	{ "pile_set_name": "StackExchange" }
= -8n. Solve 0 = nu - s + 3 - k, 3u + 3s = 21 for u. 3 Let j = 5374 - 5364. Solve o - 2r + 2 = 0, o - 8r + jr + 6 = 0 for o. -4 Let h(n) = 5n - 28. Let v be h(6). Suppose 2j + 8 = 0, -4x + x = vj - 7. Solve xq - 13 = 3t + q, -2t - 10 = -3q for t. 1 Let b = 166 - 162. Suppose -s - 15 = -bd, 6s = 3d + 3s - 9. Solve 2o = 5f + 9, -3f + 3 = -0f - do for f. -3 Let j = 9 - 21. Let n be j/60 - (-1)/(-5)-11. Suppose 6r - nr = 68. Solve -15 = -2d + 5h, r - 4 = 3d + 2h for d. 5 Suppose 1356 - 460 = 56q. Solve 3m = -4t + q, -4m + 0m = 5t - 20 for t. 4 Let r(b) = -b3 - 15b*2 - 11b - 44. Let p be r(-10). Let c = p - -456. Solve -3y + 22 = -5g, 4g + y = -y - c for g. -5 Let l = 109 + -109. Solve l = -2r + 2i - 4, 70r - 3i + 9 = 68r for r. 3 Let k(f) = -28f - 140. Let v be k(-8). Suppose 0 = -52b + 31b + v. Solve -3w + b + 2 = 3z, -z = -4w - 7 for w. -1 Suppose 61q - 1224 = 10q. Solve qz + 4w = 28z + 16, 25 = 5z + 4w for z. 1 Let b(f) = 3 + 8f3 - f3 - 7f2 - 4f - 8f3 + 2. Let c be b(-4). Let h = c - -31. Solve d - 3o = -o + 8, -hd + 2o = -20 for d. 4 Let x(t) = -t*2 + 8t + 9. Let i = -51 - -50. Let z be x(i). Solve p = -zp + 2, 5f + p + 8 = 0 for f. -2 Suppose -14 = -4x + c, 6x - x - 4c - 23 = 0. Suppose 4j = 9j - q - 72, -40 = -xj - q. Let t = -7 + 11. Solve tv = -20, -4v - j = -4n + 2 for n. -1 Let f be ((-63)/14)/((-6)/4). Suppose fb - 12b = 0. Suppose 3u - c + 0 + 4 = b, -2c + 8 = 0. Solve us + 2s + 5 = q, -q + 4s = -9 for q. 1 Let v = -167 - -233. Let c be ((-96)/v)/8 - (-180)/22. Solve 5t + 3z = 25, 0 = -cz + 4z for t. 5 Let v(t) = -t*2 - 4t - 1. Let h be v(-3). Let q = 33213 + -33212. Solve -2z = 5l + 2, -hz = 3l - 1 - q for l. -2 Let s = -26270 + 26272. Solve 3u + 2m + s = 0, 41m - 40m = u + 4 for u. -2 Let x = -16591 + 16596. Solve -i = xr + 44 - 16, 0 = 4i - 3r - 3 for i. -3 Suppose 170h - 340h + 179h = 45. Solve hx - 2v - 21 + 0 = 0, -17 = -3x - v for x. 5 Let h(c) = 3c2 - c + c2 + 0c2 - 3c*2. Let a be (28/49)/(4/14). Let i be h(a). Solve -p + 5 = d, -ip = -3d + 4 + 11 for p. 0 Let d = -149 + 282. Suppose 4z + 15 = -d. Let k = z + 40. Solve -2c - n - 7 = k, c - 6 = 5n for c. -4 Suppose -4p + z - 167 = 0, -4z = -5p - 244 + 49. Let y = p - -45. Solve yd + 4 = 5s + d, -5s = -4d - 1 for s. 1 Let r(i) = -2i*2 + 143i + 222. Let c be r(73). Solve 4y + 6 = 2x + 12, -cy + 5x = -8 for y. 1 Suppose 2c - 2t = 4c, 5t = -3c - 2. Let z be c/(-2)(1 + 1) + 3. Solve za + 10 = 2o, 4a - 9a - 21 = -o for o. 1 Let k = 258 - 255. Suppose 0 = r + 4r + 5, 3r = -3v + k. Solve -s + 4s + 21 = -3y, -17 = vs + 3y for s. -4 Let z(c) = 11c + 2c2 - 4c + 0c2. Let v be z(-5). Suppose 4y - v = -y. Solve 0 = 3g - yb - 15, 5b = 5g - 2g - 15 for g. 5 Let p = 169 + 275. Suppose -16 = 440b - pb. Solve -4i = 4y - 0y, -y = -bi for y. 0 Let h = 212 + -208. Let r(l) = 4l*2 - 12l - 4. Let v be r(h). Solve -y - 3a + 7a + v = 0, -y - 8 = a for y. -4 Let j be (3 + -4)/(3/(-84)). Suppose -24g + jg - 40 = 0. Solve 4n = 5c - g, c + 2n = -0 + 2 for c. 2 Suppose -48 + 42 = -3i. Suppose 5s - 2h = 20 + 8, -ih - 12 = -s. Solve -4y + k - 16 = -3k, sk = 0 for y. -4 Suppose -4u + 817 - 785 = 0. Suppose f + 3 = 6. Solve -3n - u = -d + 2n, fd = -2n + 7 for d. 3 Suppose -40 = -66x + 224. Solve 11 - 15 = n - 5s, xs = -n - 4 for n. -4 Suppose -19r = -462 - 466 - 212. Solve 5v - 65g - 10 = -rg, -3v - 12 = 3g for v. -1 Suppose -4d = g + 5, 3g - 11d - 15 = -8d. Solve -gs - 1 + 2 = -z, 5s - 3z + 1 = 0 for s. 1 Let b(a) = -a3 + 3a*2 + 17a + 44. Let t be b(9). Let j = -286 - t. Solve 4i = 2z + z + 26, -jz + 5i = 31 for z. -2 Let v(h) = -11h + 22. Let b be v(2). Suppose 25 = 5a, -2w + ba - 5a + 31 = 0. Suppose 2j - 1 = 1. Solve wu - j = d + 4, -u = -d - 1 for d. 1 Suppose -5i + 0d = -3d - 39, -5i = -2d - 41. Suppose r - 3r = -10. Let x = 11966 + -11950. Solve h - rm + m = x, h = -m - i for h. -4 Suppose -5j + 4y - 5y = 47, -3y = -j - 19. Let o(i) = -i*2 - 9i + 13. Let k be o(j). Suppose kb - 19 = 26. Solve h - 4v = -v + 17, 5h - b = v for h. 2 Let r(q) = 6 - 78q + 38q - 29 + 47q. Let o be r(5). Solve -39 + o = -3y - 4k, 4y = 5k + 5 for y. 5 Let q be (-375)/(-525) - (-116)/14. Solve z + 4g = 17, 0 = -2z + 9g - 12g + q for z. -3 Suppose -37575 = -445l - 1530. Solve -77y + 5f - 23 = -ly, f - 7 = -2y for y. 2 Let x be (-3 - -1)3/(-2). Let w = -68 - -71. Suppose -14z + 3 = w. Solve -r + zr + 8 = xv, -2v = 3r - 17 for v. 1 Let w be 8 + 22/(-2) - 2. Let o(x) = -12x + 52. Let d be o(w). Solve -3p + 5s + 21 = 0, ds + 12 - 2 = -p for p. 2 Suppose 11s - 13 = -68. Let l be 14/245s-56. Suppose -k = -3 - 0. Solve -a + k = p - 2a, -3p - 2a - l = 0 for p. -2 Let r be (-5)/2(16/25)/(288/(-720)). Solve 6 = 5d - f, -2d + 3f + 1 = -rd for d. 1 Suppose 54 = -13s + 93. Solve sv + h = 5, -2v = -4v + 4h + 22 for v. 3 Suppose 4x = -2x + 36. Suppose -14p + 40 = -xp. Solve -2k + 16 = -pt - k, 4k + 5 = -3t for t. -3 Let b be (-13)/3 + (-1807)/(-417). Solve -4h - 4p - 21 = 11, -3h - 2p - 19 = b for h. -3 Suppose 4h + 25d - 39 = 24d, -25 = -4h + d. Solve -3b + 2 = -n, 0 = 3n - hb + 13b + 6 for n. -2 Let z = 249 + -253. Let y be (-4 + 4)/((z + 10)/3). Solve y = -3x + 3b - 9, 0b = -4x + 3b - 10 for x. -1 Let q(o) = -3o*3 + 2o*2 - 3o - 4. Let d be q(-1). Solve -4g = 2z - d, -g - 10z + 6z = -8 for g. 0 Let d(b) = b + 10. Let x be d(-8). Let n be x/(6/(-15)) + 10. Solve 3w - 3 = 3s, -nw - 65 + 25 = 4s for w. -4 Let k be 16/(-10)(-100)/40. Let s(u) = -u + 5. Let p be s(0). Solve 5i + 10 = 4c, -3c + p = -ki - i for i. 2 Suppose 3i - 16 = 7i, -12 = -4g - 3i. Solve -a - 28 = -5n, -5a - gn = -2n - 5 for a. -3 Suppose -8x - 110 = -14x - 16x. Let o = 6 + -13. Let m = o + 9. Solve 3s - w = 1, 0 = -s - mw + xw + 11 for s. -1 Suppose 2q + 14q - 336 = 0. Suppose 8k + q = 15k. Let m = -22 + 40. Solve -x + m = kl - 0, l = -3x + 14 for l. 5 Suppose c + 5 = 0, -3a - 17c + 12c - 7 = 0. Solve an + 6 - 40 = o, n - 21 = 4o for o. -4 Suppose -13o + 39o = -26. Let y(q) = -4q3 - 5q*2 + 2q + 6. Let b be y(o). Solve 5x + bw = 0, -5w = 2x + 10 + 9 for x. 3 Let p(u) = 220u + 5063. Let g be p(-23). Solve -3 = gh - 3d + 6, 3d - 12 = 4h for h. -3 Let n = -10340 - -10340. Solve nb + 2b = -5q - 31, -2b = 3q + 21 for q. -5 Suppose 5 - 89 = -21l. Solve 4f + 2i = -28, lf + 4i + 27 + 9 = 0 for f. -5 Suppose 152 = 60n - 148. Solve 0 = 3f + 4j + 19, -3j + 2 = nf + 30 for f. -5 Let g = -5574 - -5579. Solve -4o = 5c - 17, 0 = -4o + 4c + g + 3 for o. 3 Let t be -9 - (478/(-22) - 9/33). Solve tu - 22 = 17u + 3x, 0 = -2x - 4 for u. -4 Let m(z) = z*2 + 6z - 12. Let w be (-6)/((-18)/(-4)(-34)/(-204)). Let d be m(w). Solve n - 11 = -dh, 2h + 3h = -4n for h. 4 Let z = 21021 - 21016. Solve 0 = -zk + 2h + 37 - 22, k + 5h = 30 for k. 5 Let h be (27/(-3))/((-4)/72) - 2. Let c = h + -158. Solve -4a - 17 = -3i, 3a + 8 + 4 = ci for i. 3 Let l = 34 + -29. Let c = -2688 - -2692. Solve 2v - cj + 6 = 0, 0 = -lv + 3j - 5j - 27 for v. -5 Let w(n) = -n3 - 90n*2 - 503n + 87. Let y be w(-84). Solve 4b + 16 = -yh, 4h - 9 = -b - 13 for h. 0 Suppose 738b + 160 = 758b. Solve -3n + 25 = -4x, 3x + b = -n - 1 for n. 3 Let r(u) = 2u2 - 32u + 113. Let c be r(5). Solve 5l = -5p + 3l - 17, cp = -3l - 3 for p. -5 Suppose -14s - 3 = -11s, 5s = 2r - 17. Solve 4w + 16 = -ry + 2y, -5y = -2w - 8 for y. 0 Let w(h) = h*2 + 6h + 3. Suppose 0 = 37o - 39o. Let i be w(o). Solve ij + 3 = 3z, j = -j - z - 14 for j. -5 Let c = -435 + 450. Suppose r - c = 3w - 0, -w - 5 = -5r. Solve -l - 4l + 2j - 19 = r, -3 = 3l - 4j for l. -5 Suppose 216 + 262 = 24o + 118. Solve 0 = i + 3d - o, 9d + 32 = 4i + 14d for i. 3 Let g(d) = 2d*3 + 6d*2 + 2d + 5. Let j be g(0). Solve 4m + 4 = -k, 314m - 318m + jk - 4 = 0 for m. -1 Suppose -5 = -2h + 5. Let x(i) = 20i - 56i + 34i - 6. Let g be x(-4). Solve 8 = -6w + gw - y, 0 = hw + y + 9 for w. -1 Let u(h) = 3h*2 - 24h + 5.	{ "pile_set_name": "DM Mathematics" }
public class Class1 { public Class1() { T t1 = T.Instance / T.Instance; T t2 = T.Instance / 123; } } --------------------------------------------------------- M:T.op_Division(T,T) P:T.Instance P:T.Instance M:T.op_Division(T,System.Int32) P:T.Instance	{ "pile_set_name": "Github" }
Due to rising health costs, the high costs of hospital rooms, the desire to provide comfort and convenience to patients, the medical industry has promoted in-home care for patients suffering from various maladies. Many patients must be connected to various medical devices. These medical devices frequently monitor certain parameters of the patient's health and have controls which must be adjusted due to changes in the patient's needs. Therapy changes may also require that entire protocols be programmed. In early versions of these medical devices, the physical presence of a care provider was required to adjust the device's protocol. Such reprogramming is costly and time-consuming. In addition, healthcare providers such as hospitals, and health insurance agencies paying for healthcare now often require documentation supporting all medical procedures. For example, a health insurance agency may require that a patient prove that specific parameters which measure their health are at a certain level in order for the patient to be reimbursed or the agency may require evidence that the equipment is actually being used as intended. Also, patients or their care givers at home often fail to inform the care provider that an alarm associated with a medical device has occurred and, in certain cases patients may tamper with a device in response to an alarm condition. Therefore, a need exists for a remotely or locally controllable medical device system that can inform care providers of a patient's status by notifying of alarm conditions and sending status reports to a remote fax or computer of the care provider or other health personnel.	{ "pile_set_name": "USPTO Backgrounds" }
ITAM ITAM may refer to: Instituto Tecnológico Autónomo de México, a private research university located in Mexico City, Mexico IT asset management Immunoreceptor tyrosine-based activation motif	{ "pile_set_name": "Wikipedia (en)" }
According to a Sales Associate at my local J.Crew, this sweater jacket has been flying out the door, so I wanted to show it to you while it was still available. We took these photos a couple of weeks ago, before the recent heatwave. When sweater weather returns, I’ll be ready! I really like this jacket! It’s lightweight, and a nice neutral color that “plays well with others.” It lands squarely in my Softly Structured sweet spot. The sunglasses are from Missoni, purchased in Rome. I’ve been test-driving this bag to see if it would be good for travel this fall. It’s lightweight and holds quite a bit. The horn necklace is a few years old. It’s a nice looking piece, but extremely fragile. Seems like every time it bumps against anything, one of those links breaks. You can’t see it, but there are a couple of safety pins holding it together in back. I love this sweater jacket…looks great. I am like Susan D, I still have items I did not wear last year because it was a warm season. I really hope we have a colder fall & winter because I am ready! I would wear your exact look…and probably will. Love your jacket and the colors. I would have put a deep burgundy T with your jacket since that is one of my favorite combinations. Fall is my best month for clothes. Those are my colors and I love to dress in comfortable, warm outfits. In the Northeast, autumn is gorgeous and all too short. So I embrace it and enjoy every day. You are so lucky to be able to wear those warm autumn colors so well. I have to stick to navy. And navy. And plaid. I’m still on the fence about the sweater jacket–will it pill and lose shape are what I wonder about the most. For now I’ll stick to my collection of J. Crew blazers. But the bag. I’m telling you, those leather Longchamp bags are great for travel and everyday use. You can fit everything but the kitchen sink in them. I know some aren’t fans because of the lack of compartmentalization–but if you go to Amazon you can find handbag organizers for less than twenty bucks that work like a charm. Really nice outfit in this post. Hi Catherine, the jacket is a bit more structured than a cardigan, so I’m hoping it holds shape well. Will have to let you know about that and if it pills after I’ve had a chance to wear it a bit more. With temperatures still in the low-80’s, haven’t had the opportunity. I’ve been eyeing that Lonchamp bag for a while. Have you formed an opinion? Is the one in your beautiful photo shoot red or more of a burgundy color? Was 59 degrees this morning in Austin! Now if only it would stay that way. Fall has not started in the Northwest. It is still hot and very smoky from all the fires. I wish it would hurry, because fall is my favorite season. I can hardly wait to wear sweaters ( without a coat) and walk in the crisp air. I’m really looking forward to cooler temps. This summer has been a beast. Great sweater Susan! I’ll have to check that out. It looks like a great combo of casual and elegant. I’m looking forward to wearing scarves and boots! I LOVE my leather Longchamp bag for travel and to echo Catherine…absolutely ferret out one of those interior organizer thing-ies and use it. On Amazon I also saw a piece that fits in the bottom of the bag if you want it to have a flat bottom..I can fit the purse organizer plus an iPhone and an IPad ( not a mini) AND a small water bottle and micro umbrella with room to spare. The strap is long enough to cross body ( over a parka!!) Just a word of warning, if you are not using the strap remove it and tuck it into the bag. ( do this with any purse) You see the way you have it in the top photo? Wearing it like that I caught the strap on a hand rail and came very close to falling down some subway stairs… Also a good way for a passing purse snatcher to grab your beautiful bag.. Waiting for Black Friday to get a good deal on another one… I have the gray nylon version of the Longchamp bag. (Purchase in US in 2016). Very happy with the bag and use it at home durning the weekends carrying by handles leaving the long strap on the bag. However I don’t like the bag for travel as the long strap is not adjustable. Whenever I put it cross-body it hangs low and heavy and bounces on my leg as I walk. Not attractive. I still find a knapsack is the most useful travel bag for all day on the go site seeing, museums etc. Too easy for sneak thieves to raid. I warned my DIL not to wear hers when she was in Paris but she didn’t believe me and lost her laptop as a result. She felt nothing. But it was gone when she took the backpack off. Lots of girls wear theirs on the front in Paris, if you feel strongly about day backpacks. For me a cross body bag is the best – it doesn’t have to be Longchanps. I have a super LV messenger bag which is very secure and is adjustable. And much smarter than a backpack. You kind of brand yourself as a tourist if you wear a backpack – and this draws sneak thieves’ attention. Save the backpack for water bottles and fold up umbrellas etc when walking in the countryside. Best wishes, Pamela Yes, Yael, I saw the charcoal. That would be my pic, though also Parisian leadpipe grey. I had hair the same colour as yours; it is greyer now, but the silver with black undertones remain, as does the skin. Odd nobody else mentioned the trousers – I love that deep green. Your blog looks luscious! Look at this very “alternative” Museum of Jewish Montreal: https://en.wikipedia.org/wiki/Museum_of_Jewish_Montreal which also features “kosherish” food, both Ashkenazic and Sephardic. https://www.facebook.com/museedumontrealjuif I’m not Jewish by the way. Thank you! I love the look of that museum, there is a contemporary Jewish museum in San Francisco that I love! My grey hairs started to multiply this year, and I’m so excited for more silver and gray clothing. My mother went silver around the face first and I’m hoping that’s what happens for me too – it’s like a silver halo! FOLLOW ME ON PINTEREST POPULAR POSTS DISCLOSURE This website uses affiliate links, which may generate commissions based on clicks or purchases. See my complete disclosure policy here. PRIVACY POLICY We do not share personal information with third-parties nor do we store information we collect about your visit to this blog for use other than to analyze content performance through the use of cookies, which you can turn off at anytime by modifying your Internet browser’s settings. We are not responsible for the republishing of the content found on this blog on other Web sites or media without express permission. This privacy policy is subject to change without notice.	{ "pile_set_name": "Pile-CC" }
Produced by An Anonymous Volunteer REBECCA MARY By Annie Hamilton Donnell Contents I. THE HUNDRED AND ONETH II. THE THOUSAND QUILT III. THE BIBLE DREAM IV. THE COOK-BOOK DIARY V. THE BEREAVEMENT VI. THE FEEL DOLL VII. THE PLUMMER KIND VIII. ARTICLE SEVEN IX. UN-PLUMMERED The Hundred and Oneth Rebecca Mary took another stitch. Then another. "Ninety-sevvun, ninety-eight," she counted aloud, her little pointed face gravely intent. She waited the briefest possible space before she took ninety-nine. It was getting very close to the Time now. "At the hundred an' oneth," Rebecca Mary whispered. "It's almost it." Her breath came quicker under her tight little dress. Between her thin, light eyebrows a crease deepened anxiously. "Ninety--n-i-n-e," she counted, "one hun-der-ed"--it was so very close now! The next stitch would be the hundred and oneth. Rebecca Mary's face suddenly grew quite white. "I'll wait a m-minute," she decided; "I'm just a little scared. When you've been lookin' head to the hundred and oneth so LONG and you get the very next door to it, it scares you a little. I'll wait until--oh, until Thomas Jefferson crows, before I sew the hundred and oneth." Thomas Jefferson was prospecting under the currant bushes. Rebecca Mary could see him distinctly, even with her nearsighted little eyes, for Thomas Jefferson was snow-white. Once in a while he stalked dignifiedly out of the bushes and crowed. He might do it again any minute now. The great sheet billowed and floated round Rebecca Mary, scarcely whiter than her face. She held her needle poised, waiting the signal of Thomas Jefferson. At any minute.... He was coming out now! A fleck of snow-white was pricking the green of the currant leaves. "He's out. Any minute he'll begin to cr--" He was already beginning! The warning signals were out--chest expanding, neck elongating, and great white wing aflap. "I'm just a little scared," breathed the child in the foam of the sheet. Then Thomas Jefferson crowed. "Hundred and one!" Rebecca Mary cried out, clearly, courage born within her at the crucial instant. The Time--the Time--had come. She had taken her last stitch. "It's over," she panted. "It always was a-coming, and it's come. I knew it would. When it's come, you don't feel quite so scared. I'm glad it's over." She folded up the great sheet carefully, making all the edges meet with painful precision. It took time. She had left the needle sticking in the unfinished seam--in the hundred-and-oneth stitch--and close beside it was a tiny dot of red to "keep the place." "Rebecca! Rebecca Mary!" Aunt Olivia always called like that. If there had been still another name--Rebecca Mary Something Else--she would have called: "Rebecca! Rebecca Mary! Rebecca Mary Something Else!" "Yes'm; I'm here." "Where's 'here'?" sharply. "HERE--the grape-arbor, I mean." "Have you got your sheet?" "I--yes'm." "Is your stent 'most done?" Rebecca Mary rose slowly to her reluctant little feet, and with the heavy sheet across her arm went to meet the sharp voice. At last the Time had come. "Well?" Aunt Olivia was waiting for her answer. Rebecca Mary groaned. Aunt Olivia would not think it was "well." "Well, Rebecca Mary Plummer, you came to fetch my answer, did you? You got your stent 'most done?" Aunt Olivia's hands were extended for the folded sheet. "I've got it DONE, Aunt 'Livia," answered little Rebecca Mary, steadily. Her slender figure, in its quaint, scant dress, looked braced as if to meet a shock. But Rebecca Mary was terribly afraid. "Every mite o' that seam? Then I guess you can't have done it very well; that's what I guess! If it ain't done well, you'll have to take it--" "Wait--please, won't you wait, Aunt 'Livia? I've got to say something. I mean, I've got all the over-'n'-overing I'm ever going to do done. THAT'S what's done. The hundred-and-oneth stitch was my stent, and it's done. I'm not ever going to take the hundred and twoth. I've decided." Understanding filtered drop by drop into Aunt Olivia's bewildered brain. She gasped at the final drop. "Not ever going to take another stitch?" she repeated, with a calmness that was awfuler than storm. "No'm." "You've decided?" "Yes'm." "May I ask when this--this state of mind began?" Rebecca Mary girded herself afresh. She had such need of recruiting strength. "It's been coming on," she said. "I've felt it. I knew all the time it was a-coming--and then it came." It seemed to be all there. Why must she say any more? But still Aunt Olivia waited, and Rebecca Mary read grim displeasure in capitals across the gray field of her face. The little figure stiffened more and more. "I've over-'n'-overed 'leven sheets," the steady little voice went on, because Aunt Olivia was waiting, and it must, "and you said I did 'em pretty well. I tried to. I was going to do the other one well, till you said there was going to be another dozen. I couldn't BEAR another dozen, Aunt Olivia, so I decided to stop. When Thomas Jefferson crowed I sewed the hundred-and-oneth stitch. That's all there's ever a-going to be." Rebecca Mary stepped back a step or two, as if finishing a speech and retiring from her audience. There was even the effect of a bow in the sudden collapse of the stiff little body. It was Aunt Olivia's turn now to respond--and Aunt Olivia responded: "You've had your say; now I'll have mine. Listen to me, Rebecca Mary Plummer! Here's this sheet, and here's this needle in it. When you get good and ready you can go on sewing. You won't have anything to eat till you do. I've got through." The grim figure swept right-about face and tramped into the house as though to the battle-roll of drums. Rebecca Mary stayed behind, face to face with her fate. "She's a Plummer, so it'll be SO," Rebecca Mary thought, with the dull little thud of a weight falling into her heart. Rebecca Mary was a Plummer too, but she did not think of that, unless the un-swerving determination in her stout little heart was the unconscious recognition of it. "I wonder"--her gaze wandered out towards the currant-bushes and came to rest absently on Thomas Jefferson's big, white bulk--"I wonder if it hurts very much." She meant, to starve. A long vista of food-less days opened before her, and in their contemplation the weight in her heart grew very heavy indeed. "We were GOING to have layer-cake for supper. I'm VERY fond of layer-cake," Rebecca Mary sighed, "I suppose, though, after a few weeks"--she shuddered--"I shall be glad to have ANYTHING--just common things, like crackers and skim-milk. Perhaps I shall want to eat a--horse. I've heard of folks--You get very unparticular when you're starving." It was five o'clock. They WERE going to have supper at half past. She could hear the tea things clinking in the house. She stole up to a window. There was Aunt Olivia setting the layer-cake on the table. It looked plump and rich, and it was sugared on top. "There's strawberry jam in between it," mused Rebecca Mary, regretfully. "I wish it was apple jelly. I could bear it better if it was apple jelly." But it was jam. And there was honey, too, to eat with Aunt Olivia's little fluffy biscuits. How very fond Rebecca Mary was of honey! Aunt Olivia stood in the kitchen doorway and rang the supper bell in long, steady clangs just as usual. But no one responded just as usual, and by the token she knew Rebecca Mary had not taken the other stitch that lay between her and supper. "She's a Plummer," sighed Aunt Olivia, inwardly, unrealizing her own Plummership, as little Rebecca Mary had unrealized hers. Each recognized only the other's. The pity that both must be Plummers! Rebecca Mary stayed out of doors until bedtime. She made but one confidant. "I've done it, Thomas Jefferson," she said, sadly. "You ought to be sorry for me, because if you hadn't crowed I shouldn't have sewed the hundred and oneth. But you're not really to BLAME," she added, hastily, mindful of Thomas Jefferson's feelings. "I should have done it sometime if you hadn't crowed. I knew it was coming. I suppose now I shall have to starve. You'd think it was pretty hard to starve, I guess, Thomas Jefferson." Thomas Jefferson made certain gloomy responses in his throat to the effect that he was always starving; that any contributions on the spot in the way of corn kernels, wheat grains, angleworms--any little delicacies of the kind--would be welcome. And Rebecca Mary, understanding, led the way to the corn bin. In the dark hours that followed, the intimacy between the great white rooster and the little white girl took on tenderer tones. At breakfast next morning--at dinner time--at supper--Rebecca Mary absented herself from the house. Aunt Olivia set on the meals regularly and waited with tightening heartstrings. It did not seem to occur to her to eat her own portions. She tasted no morsel of all the dainties she got together wistfully. At nightfall the second day she began to feel real alarm. She put on her bonnet and went to the minister's. He was rather a new minister, and the Plummers had always required a good deal of time to make acquaintance. But in the present stress of her need Aunt Olivia did not stop to think of that. "You must come over and--and do something," she said, at the conclusion of her strange little story. "It seems to me it's time for the minister to step in." "What can I do, Miss Plummer?" the embarrassed young man ejaculated, with a feeling of helplessness. "Talk to her," groaned Aunt Olivia, in her agony. "Tell her what her duty is. Rebecca Mary might listen to the minister. All she's got to do is to take just one stitch to show her submission. It won't take but an instant. I've got supper all out on the kitchen table--I don't care if it's ten o'clock at night!" "It isn't a case for the minister. It's a case for the Society for the Prevention of Cruelty to Children!" fumed the minister's kind little wife inwardly. And she stole away in the twilight to deal with little Rebecca Mary herself. She came back to the minister by and by, red-eyed and fierce. "You needn't go over; I've been. It won't do any good, Robert. That poor, stiff-willed, set little thing is starving by inches!" "I think her aunt is, too!" "Well, perhaps--I can't help it, Robert, perhaps the--aunt--ought--to." "My dear!--Felicia!" "I told you I couldn't help it. She is so hungry, Robert! If you had seen her--What do you think she was doing when I got there?" "Crying?" "Crying! She was laughing. _I_ cried. She sat there under some grapevines watching a great white rooster eat his supper. His name, I think, is Thomas Jefferson." "Yes, Thomas Jefferson," agreed the minister, with the assurance of acquaintance. For Thomas Jefferson was one of his parishioners. "Well, she was laughing at him in the shakiest, hungriest little voice you ever heard. 'Is it good?' she says. 'It LOOKS good.' He was eating raw corn. 'If I could, I'd eat supper with you when you're VERY hungry, you don't mind eating things raw.' Then she saw me." "Well?" "Well, I coaxed her, Robert. It didn't do any good. Tomorrow somebody must go there and interfere." "She must be a remarkably strange child," the minister mused. He was thinking of the holding-out powers of the three children he had a half-ownership in. "I don't think Rebecca Mary IS a child, Robert. She must be fifty years old, at the least. She and her aunt are about the same age. Perhaps if her mother had lived, or she hadn't made so many sheets, or learned to knit and darn and cook--" The minister's kind little wife finished out her sentence with a sigh. She took up a little garment in dire straits to be mended. It suggested things to the minister. "Can Rhoda darn?" "RHODA!" "Or make sheets and bread and things?" "Robert, don't you feel well? Where is the pain?" But the laugh in the pleasant blue eyes died out suddenly. Little Rebecca Mary lay too heavy on the minister's wife's heart for mirth. Aunt Olivia went into Rebecca Mary's room in the middle of the night. She had been in three times before. "She looks thinner than she did last time," Aunt Olivia murmured, distressedly. "Tomorrow night--how long do children live without eating? It's four meals now--four meals is a great many for a little thin thing to go without!" Aunt Olivia had been without four meals too; she would have been able to judge how it felt--if she had remembered that part. She stood in her scant, long nightgown, gazing down at the little sleeper. The veil was down and her heart was in her eyes. Rebecca Mary threw out her arm and sighed. "It LOOKS good, Thomas Jefferson," she murmured. "When you're VERY hungry you can eat things raw." Suddenly the child sat up in bed, wide-eyed and wild. She did not seem to see Aunt Olivia at all. "Once I ate a pie!" she cried. "It wasn't a whole one, but I should eat a whole one now--I think I should eat the PLATE now." She swayed back and forth weakly, awake and not awake. "Once I ate a layer-cake. There was jam in it. I wouldn't care if it was apple jelly in it now--I'd LIKE apple jelly in it now. Once I ate a pudding and a doughnut a-n-d--a--a--I think it was a horse. I'd eat a horse now. Hush! Don't tell Aunt Olivia, but I'm going to eat--to--e-at--Thom-as--Jeffer--" She swayed back on the pillows again. Aunt Olivia shook her in an agony of fear--she was so white--she lay so still. "Rebecca! Rebecca Mary! Rebecca Mary PLUMMER!" Aunt Olivia shrilled in her ear. "You get right out o' bed this minute and come downstairs and eat your supper! It's high time you had something in your stomach--I don't care if it's twelve o'clock. You get right out o' bed REBECCA MARY!" Aunt Olivia had the limp little figure in her arms, shaking it gently again and again. Rebecca's startled eyes flew open. In that instant was born inspiration in the brain of Aunt Olivia. She thought of an appeal to make. "Do you want ME to starve, too? Right here before your face and eyes? I haven't eat a mouthful since you did, and I shan't till you DO." Rebecca Mary slid to the floor with a soft thud of little brown, bare feet. Slow comprehension dawned in her eyes. "Are your---- did you say YOU was starving, too?" "Yes"--grimly. "Does it hurt you--too?" "Yes"--unsteadily. "VERY much?" "YES." "Why don't you eat something?" "Because you don't. I'm waiting for you to." "Shan't you ever?" "Not if you don't." Rebecca Mary caught her breath in a sob. "Shall I be--to blame?" She was moving towards the door now. With an irresistible impulse Aunt Olivia gathered her in her arms, and covered her lean little face with kisses. "You poor little thing! You poor little thing! You poor little thing!" over and over. Rebecca Mary gazed up into the softened face and read something there. It took her breath away. She could not believe it without further proof. "You don't--I don't suppose you LOVE me?" panted Rebecca Mary. But Aunt Olivia was gone out of the room in a swirl of white nightgown. "Everything's on the table," she called back from the stairs. "I'm going to light a fire. You come right down. I think it's high time--" her voice trailing out thinly. "She does," murmured Rebecca Mary, radiant of face. At half past twelve o'clock they both ate supper, both in their scant, white nightgowns, both very hungry indeed. But before she sat down in her old place at the table, Rebecca Mary went round to Aunt Olivia's place and whispered something rather shyly in her ear. She had been by herself in a corner of the room for a moment. "I've sewed the hundred and twoth," Rebecca Mary whispered. The Thousand Quilt "Good afternoon," Rebecca Mary said, politely. The minister's wife was cutting little trousers out of big ones--the minister's big ones. It was the old puzzle of how to steer clear of the thin places. "Boys grow so!" sighed, tenderly, the minister's wife, over her work. She had not heard the voice from the doorway. "Good afternoon"--again. It was a quaint little figure in tight red calico standing there. It might easily have stepped down from some old picture on the wall. Rebecca Mary had a bundle in her arms. It was so large that it obscured breast and face, and only a pair of grave blue eyes, presided over by thin, light brows, seemed visible to the minister's wife. The trousers puzzle merged into this one. Now who could-- "Oh! Oh, it's Miss Plummer's little girl Rebecca," she said, cordially. "Rebecca Mary her NIECE," came, a little muffled, from behind the great bundle. "Rebecca Mary's niece---- Oh, you mean Miss Plummer's niece, and your whole name is that! But I suppose she calls you Rebecca or Becky, for short? Walk in, Rebecca." But Rebecca Mary was struggling with the paralyzing vision of Aunt Olivia calling her Becky. She had passed by the lesser wonder of being called Rebecca without the Mary. "Oh no'm, indeed; Aunt 'Livia never shortens me," gently gasped the child. And the minister's wife, measuring from the bundle down, smiled to herself. There did not seem much room for shortening. "But walk in, dear--you're going to walk in? I hope you have come to make me a little call?" Rebecca Mary struggled out of her paralysis. Here was occasion for new embarrassment. For Rebecca Mary was honest. "N-o'm I mean, not a LITTLE call. I've come to spend the afternoon," she said, slowly, "and I've brought my work." The bundle--the great bundle--was her work! She advanced into the room and began carefully to unroll it. It was the turn of the minister's wife to be paralyzed. She pushed forward a chair, and the child sat down in it. "It's my Thousand Quilt that I'm making for Aunt 'Livia," explained Rebecca Mary. "It's 'most done. There's a thousand pieces in it, and I'm on the nine hundred and ninety-oneth. I thought proberly you'd have some work, so I brought mine." "Yes, I see--" The minister's wife stood looking down at the tight little red figure among the gorgeous waves of the Thousand Quilt. They eddied and surged around it in dizzy reds and purples and greens. She was conscious of being a little seasick, and for relief she turned back to the puzzle of the little trousers. It had been in her mind at first to express sorrow at Rhoda's being unfortunately away--and the boys. Now she was glad she hadn't, for it was quite plain enough that the visitor had not come to spend the afternoon with the minister's children, but with the minister's wife. "It isn't she that's young--it's I," thought the minister's wife, with kind, laughing eyes. "She's old enough to be my mother." "How old are you, dear?" she added, aloud. "Me? I guess you mean Aunt 'Livia, don't you? It's Aunt 'Livia's birthday I'm making it for, it's going to be a present. Once she gave me a present on my birthday." Once!--the minister's wife remembered Rhoda's birthdays and the boys'. Taken altogether, such a host of little birthdays! But this little old, old visitor seemed to have had but one. "My birthday is two days quicker than Aunt 'Livia's is," volunteered the visitor, sociably. "We're 'most twins, you see. Aunt 'Livia was fifty-six that time she gave me the present. She's agoing to be fifty-nine when I give her this quilt--it's taken me ever since to make it." The minister's wife looked up from her cutting. So Rebecca Mary was only fifty-nine! "It's quite a long quilt," sighed Rebecca Mary. But pride woke in her eyes as she gazed out on the splendors of the green and purple sea. "A Thousand Quilt has so many stitches in it, but when you sew'em all yourself--when you sew every single stitch--" The pride in Rebecca Mary's grave blue eyes grew and grew. "Robert," the minister's wife said that night to the minister, "it's an awful quilt, but you ought to have seen her eyes! It's taken her three years to make it--maybe you wouldn't be proud yourself!" "Maybe YOU wouldn't, if Rhoda had made it." "RHODA! Robert, she sewed one square of patchwork once and it made her sick. I had to put her to bed. Speaking of 'once' reminds me--once Rebecca Mary had a birthday present, Robert." She waited a little anxiously for him to understand. The minister always understood, but sometimes he made her wait. "Felicia, are you trying to make me cry?" he said, and she was satisfied. She went across to him, as she always did when she wanted to cry herself. The floor was strewn with the tiniest boy's engine and cars, and she remembered, as she zigzagged among them, that they had been one of his very last birthday presents. "It was--Robert, what do you think the present was? I'll give you three guesses, but I advise you to guess a rooster." "Thomas Jefferson," murmured the minister, as one who was acquainted. "Yes, that is his name. How did you remember? She is very fond of him--he is her intimatest friend, she says. So she is under great obligations to her aunt. It's a large quilt, but it's none too large to 'cover' Thomas Jefferson. I'm going to help her buy a lining and cotton batting." "Cracked corn will make a good lining, but cotton bat--" "Robert, this is not a comedy! If you'd seen Rebecca Mary, and the quilt, you'd call it a tragedy. You couldn't surprise me any if you told me she'd quilted it herself!" Down the road from Aunt Olivia's farm, across its southern boundary fence, romped and shouted all day long the Tony Trumbullses. No one, except possibly their mother, was quite certain how many of them there were; it was a dizzy process to take their census. They were never still, in little brown bare limbs nor shrill voices. From sunup to sundown the Tony Trumbullses raced and laughed. Certainly they were happy. The minister's wife had not dared to tell her Caller of the afternoon that the minister's children were down there shouting and racing with the little Tony Trumbullses. Dear, no!--not after Rebecca Mary in the course of conversation had said that Aunt Olivia did not countenance the Tony Trumbullses. Rebecca Mary did not say "countenance," but it meant that. "Her aunt won't let her play with them, Robert. And she'd like to--you needn't tell me Rebecca Mary wouldn't like to! I saw it in her poor little solemn eyes. Besides, she said she asked her aunt once to let her. Robert, aunts are cruel; I never knew it before. They've no business bringing up little Rebecca Marys!" "My dear! Felicia!" But in the minister's eyes was agreement. Aunt Olivia took afternoon naps with punctilious regularity--Aunt Olivia herself was punctilious regularity. At half past one, day upon day, she hung out the dish towel, hung up her kitchen apron, and walked with unswerving course into her bedroom. There, disposed upon the dainty bed in rigid lines of unrest, she rested. The naps were often long ones. A little after the afternoon that Rebecca Mary spent at the minister's the birthday quilt was finished. The thousandth tiny piece was neatly over-'n'-overed to its gorgeous expanse. But Rebecca Mary was not content. She longed to make it complete. She wanted to surprise Aunt 'Livia with it, as Aunt 'Livia on that momentous birthday of her own had surprised her with the little fluff-ball of yellow down that had grown into Thomas Jefferson. That had been such a beautiful surprise, but this--Aunt 'Livia had seen the quilt so many, many times! She had taught Rebecca Mary's stiff little fingers to set the first stitches in it; she had made her rip out this purple square and that pink-checked one, and this one and that one and that. Oh, Aunt 'Livia was ACQUAINTED with the quilt! It would not be much of a surprise. But Rebecca Mary set her little pointed chin between her little brown palms and pondered, and out of the pondering grew a plan so ambitious and so daring that Rebecca Mary gasped in the throes of it. But she held her ground and entertained it intrepidly. She even grew on friendly terms with it in the end. Here was a way to surprise Aunt 'Livia; Rebecca Mary would do it! That it would entail an almost endless amount of work did not daunt her: Rebecca Mary was a Plummer, and Plummers were not to be daunted. The long vista of patient hours of trying labor that the plan opened up before her set her blood tingling like a warrior's on the eve of battle. What were long, patient hours to a Plummer? Rebecca Mary girded up her loins and went to meet them. Thereafter at Aunt Olivia's nap times Rebecca Mary disappeared. Day upon day, week upon week, she stole quietly away when the door of Aunt Olivia's bedroom shut. The first time she went oddly loaded down with what would have appeared--if there had been any one for it to "appear" to be a bundle of long sticks. She made two trips into the unknown that first day. The second time the bundle looked much like that one over which her grave blue eyes had peered at the minister's wife when she went to spend the afternoon with her. It was spring when the mysterious disappearances began. It was summer before Aunt Olivia woke up--not from her nap, but from her inattention. Quite suddenly she came upon the realization that Rebecca Mary was not about the house; nor about the grounds, for she instituted prompt search. She went to all the child's odd little haunts--the grapery, the orchard, the corn-house, even to her own beloved back yard, full of sweet-scented hiding-nooks dear to a child, but sacred ground to Aunt Olivia. Rebecca Mary sometimes did her "stents" there as a special privilege; she might be there now, unprivileged. Aunt Olivia's back yard was almost as full of flowery delights to Rebecca Mary as it was to Aunt Olivia. The child was not there--not anywhere. Aunt Olivia sought for Thomas Jefferson to inquire of him, but Thomas Jefferson was missing too. She went the rounds again. Where could the child be? It was a hot, stinging day in late June when Aunt Olivia's suspicions awoke. They had been long in rousing, but, once alert, they developed rapidly into certainties. Her pale eyes glistened, her thin nostrils dilated--Aunt Olivia's whole lean, sharp, unemotional person put on suspicion. The child had gone to see the Tony Trumbullses. "My land!" ejaculated Aunt Olivia, "after all my forbidding! And she a Plummer!" She sat down suddenly as though a little faint. She had never known a Plummer to disobey before; it was a new experience. It took time to get used to it, and she sat still a long time, rigid and grim, on the edge of the chair. Then as suddenly as she had sat down she got up. It could not be--she refused to entertain the suspicion longer. Rebecca Mary had NOT gone there to that forbidden place; she was in the garden somewhere. Aunt Olivia, a little stiff as if from a chill, went once more in search of the child. "Rebecca! Rebecca Mary!" she called, at regular intervals. Then sharply, "Rebecca Mary Plummer!" Her voice had thin cadences of suspicion lurking in it against its will. But there seemed really no doubt. One by one incriminating circumstances occurred to Aunt Olivia. Rebecca Mary had longed to go so much; the Tony Trumbullses, one at a time or in a tumultuous body, had urged her so often; she herself had more than once caught the child gazing wistfully, in passing by, at the bewildering, deafening, frolics of the little Tony Trumbullses. Once Rebecca Mary had asked to go barefoot, as they went. Once she had let out the tight little braids in her neck and rumpled her thin little hair. Once Aunt Olivia had come upon her PLAYING. The remembrance of it now tightened the lines around Aunt Olivia's lips. The child had been running wildly about the yard, shouting in a strange, excited, ridiculous way. When Aunt Olivia in stern displeasure had demanded explanations, she had run on recklessly, calling back over her shoulder: "Don't stop me! I'm a Tony Trumbull!" "My land!" breathed Aunt Olivia, taking back the suspicion to her breast. "After all my forbidding she's gone down there. She's BEEN going down there dear knows how long. She's waited till I took my naps an' then went. A PLUMMER!" There was really nowhere else she could have gone. She had never wanted to go anywhere else, except to the minister's, and Rebecca Mary was punctilious and would not think of going THERE again till the minister's wife had returned her visit. But Aunt Olivia waited. As usual, she went to her room next day at nap time and closed the door behind her. But when a little figure slipped down the road towards the forbidden place a moment later, she was watching behind her blinds. She was groaning as if in pain. The little figure began to run staidly. Aunt Olivia groaned again. The child was in a hurry to get there--she couldn't wait to walk! There was guilt in every motion of the little figure. "And she runs like a Plummer," groaned Aunt Olivia. The next day, and the next, Aunt Olivia watched behind her blinds. The fourth day she put on her afternoon dress and followed the hurrying little figure. Not at once--Aunt Olivia did not hurry. There was a sad reluctance in every movement. It seemed a terrible thing to be following Rebecca Mary--Rebecca Mary Plummer to a forbidden place. Afar off Aunt Olivia heard faintly the shoutings that always heralded an approach to the Tony Trumbullses, and shuddered. The tumult kept growing clearer; she thought she detected a wild, excited little shout that might be Rebecca Mary's. Her thin lips set into a stern, straight line. A splash of red caught Aunt Olivia's eye as she drew nearer the joyous whirl of little children. Rebecca Mary wore a little tight red dress. The coil seemed closing in about the child. Close to the southern boundary fence of Aunt Olivia's land stood an old empty barn. It had been a place for storing surplus hay, once, when there had been surplus hay. For many years now it had been empty. As Aunt Olivia approached it she noticed that its great sliding door was open. Strange, when for so long it had been shut! "If that old barn door ain't open!" breathed Aunt Olivia, stopping in her astonishment. "I ain't seen it open before in these ten years. Now, what I want to know is, who opened it? Likely as not those screeching little wild Injuns." She strode across the stubby grass-ground to the barn and peered into its cool, dim depths. Then Aunt Olivia uttered a little, bewildered cry. Gradually the dimness took on light and the whole startling picture within unfolded itself to her astonished eyes. Rebecca Mary was quilting. She was stooping earnestly over a gay expanse of purples and reds and greens. Her little tight red back was towards Aunt Olivia; it looked bent and strained. Rebecca Mary's eyes were very close to the gay expanse. Suddenly Rebecca Mary began to speak, and Aunt Olivia's widened eyes discovered a great, white rooster pecking about under the quilt. His big, snowy bulk stood out distinct in the shadow of it. "I'm glad we're 'most through. Aren't you, Thomas Jefferson? It's been a pretty LONG quilt. You get sort of tired when you quilt a LONG quilt. It makes your back creak when you unbend it; and when you quilt in a barn, of course you can't see without squinching, and it hurts your eyes to squinch." Silence again, except for the industrious peck-peck of the great white rooster. Aunt Olivia stood very still. "You've been a great help, Thomas Jefferson," began again the voice of Rebecca Mary, after a little. "I'm very much obliged to you, as I've said before. I don't know what I should have done without you. No, you needn't answer. I couldn't hear a word you said. You can't hear with cotton in both o' your ears," Rebecca Mary sighed. There was no cotton in Aunt Olivia's ears to shut out the soft little sound. "But of course you have to wear it in, on account o' your conscience. It's conscience cotton, Thomas Jefferson. I've explained before, but I don't know's you understood. It seems a little unpolite to wear it in my ears, with you here keeping me comp'ny. I s'pose you think it's un--unsociable. But Aunt Olivia doesn't allow me to 'sociate with the Tony Trumbullses. Oh, Thomas Jefferson, I wish she'd allow me to 'sociate!" Aunt Olivia found herself wishing she had conscience cotton in both o' her ears. "They're such nice, cheerful little children! It makes you want to go right over their fence and hollow too." Rebecca Mary pronounced it "hollow" with careful precision. Aunt Olivia would not approve of "holler." "And when you can't, you like to listen. But I s'posed listening to them hollow would be 'sociating. So I put the cotton in." The joyous "hollowing" broke in waves of glee on Aunt Olivia's eardrums. It seemed to be assaulting her heart. Oddly, now it did not sound unmannerly and dreadful. It sounded nice and cheerful. A Plummer, even, might be happy like that. "Cotton is a very strange ex--exper'ence, Thomas Jefferson," ran on the little voice. "At first you 'most can't stand it, but you get over the worst of it bymeby. Besides, we're getting 'most through now. Ain't that splendid, Thomas Jefferson? And it's pretty lucky, too, because Aunt 'Livia's birthday is getting very near. It--it almost scares me. Doesn't it you? For I don't know how Aunt 'Livia looks when she's pleased--you think she'll look pleased, don't you, Thomas Jefferson? It's such a long quilt, and when you've sewed every stitch yourself--" If Rebecca Mary had turned round then she would have seen how Aunt Olivia looked when she was pleased. But the little figure at the quilting-frame bent steadily to its task, only another soft sigh stealing into Aunt Olivia's uncottoned ears. Thomas Jefferson pecked his way towards the open door, and the lean figure there started back guiltily; Aunt Olivia did not want to be recognized. "You there under the quilt, Thomas Jefferson?" The little voice put on tenderness. "Because I'm a-going to tell you something. Once Aunt 'Livia gave ME a birthday present and it was YOU. Such a little mite of a yellow chicken! That's why I'm making the quilt for Aunt 'Livia. It was three years ago; I've loved you ever since," added Rebecca Mary, simply. For an instant Aunt Olivia stopped being a Plummer. A sob crept into her throat. "Rebecca! Rebecca Mary! Rebecca Mary Plummer!" she cried, involuntarily. Then she stepped back hastily, glad for the cotton in Rebecca Mary's ears. For the surprise--she must not spoil the child's hard-earned surprise. And, besides, Aunt Olivia wanted to be surprised. It was a relief to get away. She could not look any longer at the picture in the great cobwebby barn--the gorgeous quilt spread out to its full extent, the empty scaffolds above Rebecca Mary stooping to her work, Thomas Jefferson pecking about the floor. Aunt Olivia was not old; through all the years ahead of her she would remember that picture. She went straight to the southern boundary fence and looked across at the jubilant little Tony Trumbullses. The one in a red dress like Rebecca Mary's she singled out with a pointing finger. "YOU come here," she called. "I won't hurt you; no need to look scairt. Do you know who I am? I'm Rebecca Mary's aunt. You know who Rebecca Mary is, don't you?" "Gracious!" shrilled the little red Tony Trumbull, which Aunt Olivia took for yes. "Well, then, you know where I live. You see here--I want you all, the whole kit o' you, to come to my house tomorrow morning to see Rebecca Mary. I'm going to say it over again. Tomorrow morning, to see Rebecca Mary!" setting apart the syllables with the pointing finger. "You can play in my back yard," said Aunt Olivia, sublimely unconscious of slang. The Bible Dream Rebecca Mary sat on the kitchen steps, shelling peas and trying not to listen. She had begun a hummy little tune to help out, but in the interstices of rattling peas and the verses of the tune she could distinctly hear some of the things Aunt Olivia and the Caller were saying. This was one of the things: "She's offered a reward, but _I_ don't calculate there's much chance she'll ever see it again." A sigh followed. The voice was the Caller's, the sigh Aunt Olivia's. "It's queer where it ever went to!" Aunt Olivia's voice. "Yes, it's all o' QUEER," the Caller's, with mysterious hints in it that made Rebecca Mary, out on the doorsteps, shudder suddenly and forget where she was in the tune. Oh, oh, dear, did they s'pose--they couldn't s'pose it had been STOLEN? Rebecca Mary's little hard brown hand stopped halfway to the pea-basket and fell limply at her side on the doorstep. It made a little thud as it fell. Rebecca Mary's horrified gaze wandered out into the glare of sunshine where wandered Thomas Jefferson, stepping daintily, hunting bugs. That was his day's work. Thomas Jefferson was a hard worker. The voices went on, but Rebecca Mary did not heed them now; she was looking at Thomas Jefferson, but she did not see him. Not until--it happened. On a sudden Thomas Jefferson, forgetful of dignity, made a swoop for something that glittered in the grass. Then Rebecca Mary saw him--then started to her feet with an inarticulate little cry, while in her honest brown eyes the horror grew. Oh, oh, dear, what was that Thomas Jefferson had swooped for? For a brief instant it had glittered in the grass--Rebecca Mary knew in her soul that it had glittered. Thomas Jefferson stretched his sheeny neck, curved it ridiculously, and crowed. It sounded like a crow of triumph; that was the way he crowed when the bug had been a delicious one. The Caller was coming out, Aunt Olivia with her. Rebecca Mary could hear the crackle of their starched skirts; Aunt Olivia's crackled loudest. Rebecca Mary had always had a queer feeling that Aunt Olivia herself was starched. There had never been a time when she could not remember her carrying her head very stiffly and straight and never bending her back. Nobody else in the world, Rebecca Mary reflected proudly, could pick up a pin without bending. SHE couldn't, herself, even after she had privately practiced a good deal. "Good afternoon, Rebecca Mary; you out here?" the Caller nodded pleasantly. Folks had such queer ways of saying things. How could you say good afternoon to anybody if she WASN'T here? "Didn't you hear Mrs. Dixey, Rebecca Mary? I guess you've forgot your manners," came in Aunt Olivia's crisp tones. "Oh yes'm, I have. I mean I DID. Yes'm, thank you, I'm out here," quavered Rebecca Mary. She was not afraid of the Caller and she had never been afraid of Aunt Olivia, but the horror that was settling round her heart made her clear little voice unsteady. Her eyes were still following Thomas Jefferson on his mincing travels about the yard. The sunshine was on his splendid white coat, but Rebecca Mary felt no pride in him. "Ain't that the han'somest rooster! You ought to show him at the fair, I declare! See how his feathers glisten in the sun!" "Thomas Jefferson belongs to Rebecca Mary," Aunt Olivia said, briefly. "She raised him." "My! Well, he's han'some enough. Ain't it amusing how a nice-feeling rooster like that will go stepping round as if he felt about too toppy to live! He'd ought to wear diamonds." "Oh, oh, dear, please don't!" breathed Rebecca Mary, softly, but neither of the women heard her. "Well, well, I must be going. I've made a regular visit. But I tell John when I get away from home, it feels so good I STAY! 'I don't get away any too often,' I says, 'and I guess I've earnt the right.' Well, I must be going if I'm ever going to! Good-bye, Miss Plummer--good-bye, Rebecca Mary. All is, I hope Mis' Avery's boarder'll find her diamond, don't you? But I don't calculate she will. Well, good afternoon. She hadn't ought to have wore the ring, when she knew it was loose in the setting like that. Some folks are just that careless! Well--" But Rebecca Mary did not hear the rest of the Caller's leave-taking. She had slipped away to Thomas Jefferson out in the sun. "Oh, come here--come here with me!" she cried, intensely. "Come out behind the barn where we can talk. I've got to say something to you that's awful! I've GOT to, you've got to listen, Thomas Jefferson." It was still and terribly hot in the treeless glare behind the barn, but it was all in the day's work to Thomas Jefferson. Behind the barn was a beautiful place for bugs. "Listen! Oh, you poor dear, you've got to listen!" Rebecca Mary cried. "You've got to stop hunting for bugs--and don't you dare to crow! If you crow, Thomas Jefferson, it will break my heart. I don't s'pose you know what you've done--I don't know as you've done it--but there's something awful happened. Oh, Thomas Jefferson, it glittered--I saw it glitter!" Suddenly Rebecca Mary stooped and gathered Thomas Jefferson into her arms. She held him with a passionate clasp against her flat little calico breast. He was HERS. He was all the intimate friend she had ever had. He had been her little downy baby and slept in her hand. She had fed him and watched him grow and been proud of him. He was her all. "Oh, Thomas Jefferson, Thomas Jefferson, what was it that glittered in the grass? Tell me and I'll believe you. Say it was a little piece o' glass and I'll put you down and go get you some corn, and we'll never speak of it again. But don't look at me like that--don't look at me like that! You look--GUILTY!" She rocked him in her arms. In her soul she knew what it was that had glittered. But in Thomas Jefferson's soul--oh, they could not blame Thomas Jefferson! "You haven't got any soul, poor dear; poor dear, you haven't got any soul, and you can't be guilty without a soul. They couldn't--hang--you." Her voice sank to the merest whisper. She tightened her clasp on the great, soft body and smoothed the soft feathers with a tender, tremulous little hand. "The Lord didn't put anything in you but a stomach and a--a gizzard. He left your soul out and you're not to blame for that. I don't blame you, Thomas Jefferson, and of course the Lord don't. But Mrs. Avery's boarder--oh, oh, dear, I'm afraid Mrs. Avery's boarder will! You mustn't tell--I mean I mustn't. Nobody must know what it was that glittered in the grass. Do you want to be--searched? "You know 'xactly where she sat over to this house yesterday morning, when she went by--and how she said you were too sweet for anything--and how she flew her hand round with--with IT on it. You know as well as I do. And it was loose, the di'mond-stone was loose. We didn't either of us know that. We're not to blame if things are loose, and you're not to blame for not having any soul. But oh, oh, dear, how dreadfully it makes us both feel! You'd better give up crowing, Thomas Jefferson; I feel just as if you'd let it out if you crew." At tea Rebecca Mary played with her spoon, while her berries swam, untasted, in their yellow sea of cream. Aunt Olivia remonstrated. "Why don't you eat your supper, child?" she asked, sharply. Rebecca Mary was always glad when she said child instead of Rebecca Mary, for then the sharpness did not cut. She was feeling now for the glasses up in her thin gray hair. Aunt Olivia could see everything through those glasses and it made Rebecca Mary tremble to think--oh, oh, dear, suppose she should see the secret hidden in Rebecca Mary's soul! It seemed as if Aunt Olivia trained the glasses directly upon the corner where the secret glittered in the gra--was hidden in Rebecca Mary's troubled little soul. But this is what Aunt Olivia said: "It's your stomach. What you need is a good dose of camomile tea to tone you up. I didn't give you any this spring, for a wonder. Now you go right up to bed and I'll set some to steeping. Does it hurt you any?" "Oh yes'm," murmured Rebecca Mary, sadly, but she meant her soul and Aunt Olivia meant her stomach. She mounted the steep stairs to her little eavesdropping room and slipped her small spare body out of her clothes into her scant little nightgown. It was rather a relief to go to bed. If she could have been sure that Thomas Jefferson--but, no, Thomas Jefferson was not in bed. As Rebecca Mary lay and waited for her camomile tea she was certain she could hear him stepping about under the window. Once he came directly under and "crew," and then Rebecca Mary hid her head in the pillow for he was letting it out. "Cock-a-doodle-do--ooo, did-you-see-me-swoo-oo-OOP-it-up?" crowed Thomas Jefferson, under the window. Rebecca Mary with her eyes pillow-deep could see him stretching his neck and letting it out. It seemed to her everybody could hear him--Aunt Olivia downstairs, steeping camomile 'blows, and Mrs. Avery's boarder across the fields. "Aunt Olivia," whispered Rebecca Mary, while she sipped her bitter tea a little later, "how much--I suppose precious things cost a great deal, don't they?" "My grief!" Aunt Olivia set down the bowl and felt of Rebecca Mary's temples, then of her wrists. The child was out of her head. "Di'mond-stones like--like that boarder's--I suppose those cost a great deal? As much as--how much as, Aunt Olivia?" "My grief, don't you worry about any di'mond-stones! YOU haven't lost any. What you'll lose will be your health, if you don't swallow down the rest o' this tea and go right to sleep like a good girl! No, no, I'm not going to answer any questions. Drink this; swallow it down." Rebecca Mary swallowed it down, but she did not go right to sleep like a good girl. She lay on the hard little bed and thought of many things, or of one thing many times. Over and over, wearily, drearily, until the sin of Thomas Jefferson became her sin. She adopted it. When at last she dropped to sleep it was to dream a Bible dream. Usually Rebecca Mary liked to dream Bible dreams, but not this one. This one was different. This one was of Abraham and Isaac. She thought she was right there and saw Abraham build the little altar and offer up--no, it wasn't Isaac! It was Thomas Jefferson. And the Abraham in her dream was turning into HER. The flowing white robes were dwindling to a little scant white nightgown. She stood a little way off and saw herself offering up Thomas Jefferson. It was a dreadful dream. The night was a perfectly black one, the kind that Rebecca Mary was afraid of. It was the only thing in the world she had ever been afraid of--a black night. But after the dream she got up stealthily and slipped through the blackness, out to Thomas Jefferson. It was only out to the little lean-to shed, but it seemed a very long way to Rebecca Mary. The blackness pressed up against her, she put out her little, trembling hands and pushed through it. "Thomas Jefferson! Thomas Jefferson!" she called softly. But he was a sound sleeper, she remembered; she would have to find him and wake him. In the darkness she felt about on Thomas Jefferson's perch for Thomas Jefferson. When the little groping hand came upon something very soft and warm, the other hand went up to join it, and together they lifted Thomas Jefferson down. He gave a protesting croak, and then, because he was acquainted with the clasp of the two small hands, and night or day liked it, he went back to his interrupted dreams and said not another word. Thomas Jefferson had never dreamed a Bible dream--never heard of Abraham or Isaac, had no soul to be disquieted. With her burden against her breast Rebecca Mary pushed back through the darkness, up to the black little room under the eaves. She felt about for her little carpet-covered shoe box and gently crowded the great white bulk into it. Then she crept back into bed and lay on the outer edge with her loving, light little hand on Thomas Jefferson's feathers. The trouble in her burdened soul poured itself out. "Oh, Thomas Jefferson," she whispered down to the heap of soft feathers, "I'm going to smooth you this way all night for tomorrow you die!" Her voice even in a whisper had a solemn, inspired note. "There's no other way; you'll have to make up your mind to be willing. It's going to break my heart, and, oh, I'm afraid it will break yours! I'm afraid it will kill us both!" Thomas Jefferson uttered a mournful little croaky sound that might have been "ET TU, BRUTE?" It pierced Rebecca Mary's breast. "There, hush, poor dear, poor dear, and rest. You'll need all your sleep," she crooned softly and brokenly. "Tomorrow morning I'll give you some beautiful corn, and then--and then I'm going to take you to Mrs. Avery's boarder and tell her the worst. I'm going to give you up, Thomas Jefferson; and I'm the best friend you've got in the world! But I've got to, I've got to--I've got to! It's been revealed to me in a dream. There was a man once in the Bible, named Abraham, and there was his dearly beloved little boy named Isaac. And now here's me named Rebecca Mary, and dearly beloved you named Thomas Jefferson. Oh, I don't suppose you can understand; I suppose you're asleep. You'll never know how it feels to give up your dearly belovedest, but oh, oh, dear, you'll know how it feels to be given up! You'll be one o' the blessed martyrs, Thomas Jefferson--doesn't that comfort you a little speck? Oh, why don't you wake up and be comforted? "The Lord excused Abraham, after all. But this isn't the Lord, it's Mrs. Avery's boarder. I'm afraid she isn't the Lord's kind--I'm afraid not, Thomas Jefferson. I don't dare to let you hope; I've got to prepare you for the worst." She caught up the big, white fellow with sudden, irresistible yearning and sat up with him and rocked him back and forth in her arms. She began a muffled, sad little tune like a wail. The words were terrible words. "I'll hold you in my arms. I'll rock you--rock you--rock you. For tomorrow, oh, to-MOR-row you--must--die! Aber-a-ham offered Isaac, and _I_-MUST OFFER YOU." Over and over, then tenderly she lowered Thomas Jefferson to the shoe box again. When Aunt Olivia came up in the morning, vaguely alarmed because it was so late and no Rebecca Mary stirring, she had news to tell. Someone going by had told her something. "Well, that woman's found her 'di'mond-stone,'--how are you feeling this morning, child? It was in her pocket where she'd put her hand in and felt round! So all that fuss for noth--" Suddenly Aunt Olivia stopped, for without warning, out of a box at the bedside stalked a great white rooster and flew to the foot board and "crew": "Cock-a-doodle-do-ooo! It was glass that glittered in the grass, And all the time I knew-oo-ooo!" "My grief?" Aunt Olivia gasped. The Cookbook Diary Rebecca Mary decided to keep a diary. It was not an inspiration, though it was rather like one in its suddenness. Of course she had always known that Aunt Olivia kept a diary. When she was very small she had stretched a-tiptoe and with little pointing forefinger counted rows and rows of little black books that Aunt Olivia had "kept." Each little black book had its year-label pasted neatly on the back. Rebecca Mary breathed deep breaths of awe, there were so many of them. There must be so much weather in those little black books--so many pleasant days, rainy days, storms, and snows! It was Rebecca Mary who remembered that it was Tuesday, and that it had showered a little Wednesday--shone Thursday--showered again on Friday. Rebecca Mary was the jog to Aunt Olivia's memory. It gave her now, at the beginning of her own diary career, an experienced feeling, as if she knew already how to keep a diary. It made it seem a much simpler matter to begin. And then, of course, the minister's littlest little boy--really it was the minister's littlest little boy who had started Rebecca Mary. He had volunteered a peep into his own diary, and made whispered explanations and suggestions. He let Rebecca Mary read some of the entries: "MUNDY, plesent and good. TUSDY, rany and bad. WENSDY, sum plesent and not good enuf to hirt. THIRSDY" but he had hastily withdrawn the book at "Thirsdy," and a tidal-wave of warm red blood had flowed up over his little brown ears and in around all the little brown islands of his freckles. So Rebecca Mary had begun hastily to talk of other things. For the minister's littlest little boy had explained that the first Statement in each entry referred to the weather and the second to the deportment of the writer, and Rebecca Mary had remarked a sympathetic resemblance between the two statements. She had caught a fleeting glimpse of the weather part of "Thirsdy"--she could guess the rest. Better let the curtain fall on "Thirsdy." On her way home Rebecca Mary decided to keep a diary herself. Her first day's record had been a good deal like the "Mundy" of the minister's littlest little boy, only there were more a's in the weather. After that, little by little, she branched out into a certain originality--the Rebecca Mary sort. If she had not been hampered by circumstances, it would have been easier to be original. The most hampering circumstance was the cookbook itself, which she was driven to use in her new undertaking. There was room on the blank leaves and above and below the recipes for cake and pudding and pie. The book was one Aunt Olivia had given her long ago to draw impossible pictures in. In the beginning Rebecca Mary tried pasting pieces of "empty" paper over the pies and puddings and cakes, but the empty paper was too transparent. In rather startling places things were liable to show through. As: "SUNDAY.--It rained a level teaspoonful. Aunt Olivia and I went to church. The text was thou shalt not steal 1 cups of sour milk--" Rebecca Mary got no farther than that. She was a little appalled at the result thus far, and hastily turned a page and began again in a blank space where no intrusive pudding could break through and corrupt. Thereafter she wrote above and below the recipes and pasted no more thin veils over them. It seemed safer. Aunt Olivia, apparently oblivious to what was going on, yet saw and did not disapprove. It was to be expected that the child should come into her inheritance sometime, early or late. If early--well. "It's the Plummer in her. All the Plummers have kept diaries," Aunt Olivia mused, knitting stolidly on while the child stooped painfully to her self-imposed task. The quaint resemblance to herself at her own diary-writing did not escape her, and she smiled a little in the Aunt Olivia way that scarcely stirred her lips. Aunt Olivia smiled oftener now when she looked at the child. She was "failing" a little, Plummerly. Between the two of them, little Plummer and big, stretched of late a tie woven of sheets and a gorgeous quilt of a thousand bits. It was not very visible to the naked eye, but they were both rather shyly conscious that it was there. They would never be quite so far apart again. Rebecca Mary took her diary out to the haunts of Thomas Jefferson and read aloud selections to him, with an odd, conscious little air, as though she were graduating. The great white fellow was a sympathetic auditor, if silence and extreme gravity count. Only once did he ever make comments, and Rebecca Mary could never quite make up her mind whether he laughed then or applauded. When a great white rooster elongates his neck, crooks it ridiculously, flaps his wings and crows, it's hard telling exactly what feeling prompts him. But Rebecca reasoned from past experience and her faith in him--he had never laughed at her before. It was applause. The especial entry which evoked it was the one that first mentioned an allowance. "'THURSDAY.--I think I'm going to--'" read Rebecca Mary slowly; and it was significant that on this Thursday there was no weather. "'I havent desided--I don't KNOW, but I think I'm going to ask Aunt Olivia to pay me 5 cents a weak. Rhoda says you call it an alowance, and I supose she knows. She is the minnister's daughter. She has 10 cents a weak unless shes bad and then she pays the minnister an alowance. He charges her 1 cent a sin and he gives it to somebody who is indignant--I think Rhoda said indignant. Then I should think he would give it back to Rhoda. I shant only ask Aunt Olivia for 5 cents--I think she will be more likely. I havent desided but I THINK I shall ask her tomorrow after her knap. After knaps you are more rested and maybe things don't look just as they do before knaps. "'FRIDAY.--I think Ide better wait untill tomorrow. Her knap was rather short. Ive desided to say you needent alow but 4 if 5 is too mutch. If she alows Im going to buy me some crimpers. Rhodas curls natchurally but she says you can crimp it if it doesent. I have begun to look at myself in the glass and it fritens me--I guess there ought to be a gh in that--to see how homebly I am. I wonder if it doesent kind of scare Aunt Olivia. Prehaps if I was pretty like Rhoda she would call me darling and dear instead of Rebecca Mary. I dont blame her mutch because I LOOK like Rebecca Mary. "'SATURDAY.--I think Sunday will be the best time to ask her, just after she gets home from meeting and has rolled her bonnet strings up, espesialy if the minnister preaches on the Lord lovething a cheerful giver. I am hopeing he will. If I dont get the crimpers Ime going to give up looking in the glass. For I think Ime growing homeblyer right along. Theres something the matter with my nose. Rhodas doesent run up hill. I never thought about noses before. Aunt Olivias is a little quear too but I like it became its Aunt Olivias nose. I wish I knew if Aunt Olivia liked mine. I wish we were better akquainted. "'SUNDAY.--I wish the Lord had created mine curly because I dont dass to ask Aunt Olivia. I don't dass to, so there. It scares my throat. I supose its because aunts arnt mothers--seems as if youd dass to ask your MOTHER. I hate to be scart on acount of being a Plummer. Im afraid Im the only Plummer that ever was--'" The reading suddenly stopped here. This was Sunday, and the last entry was fresh from Rebecca Mary's pencil. "Thomas Jefferson!" stormed Rebecca Mary, in a little gust of passion, "don't you ever TELL I was scared! As long as you live!--cross your heart!--oh, I wish I hadn't read that part to you! You're a Plummer too, and you never were scared, and you can't understand--" The diary was clutched to Rebecca Mary's little flat breast, and with a swirl of starched Sunday skirts the child was gone. She went straight to Aunt Olivia. Red spots of shame flamed in both sallow little cheeks; resolution sat astride her little uphill nose. She could not bear to go, but it was easier than being ashamed. The pointing fingers of all the Plummers pushed her on. Go she must, or be a coward. Long ago--it seemed long to Rebecca Mary--she had stood up straight and stanch and refused to make any more sheets. Was that little girl who had dared, THIS little girl who was afraid? Should that little girl be ashamed of this one? "Aunt Olivia," steadily, though Rebecca Mary's heart was pounding hard--"Aunt Olivia, are--are you well off?" She had not meant to begin like that, but afterwards she was glad that she had. "My grief!" Aunt Olivia ejaculated in her surprise. What would the child ask next? "Am I well off? If you mean rich, no, I ain't." "Oh! Then you're--why, I didn't think about your being poor! I shouldn't have thought of asking--that makes a great difference. I never thought of THAT!" She was off before Aunt Olivia had fully recovered her breath, and the stumping of her heavy little shoes going upstairs was the only distinctly audible sound. In her own room Rebecca Mary stopped, panting. "Oh, I'm glad I didn't get as far as ASKING!" she breathed aloud. "I never thought about her being poor--of course then I wouldn't ask!" But she squared her shoulders and stood up, straight and unashamed. For she had vindicated herself. She had been ready to ask. She could look that other little girl of the sheets in the face. The Other Little Girl was there, coming to meet her as she advanced to the little looking glass above the table. But Rebecca Mary waved her back peremptorily. "Go right back!" she said. "I only came to tell you I wasn't a coward--that's all. Good-bye. For I'm not coming any more. You're sorry I'm homely, and I'm sorry you are, but it doesn't do any good for us to look at each other and groan. It will make us unsatisfied. So I shall turn you back to the wall--good-bye." But for a very [long] instant they looked sadly into each other's little lean brown-yellow faces. It was a brief ceremony of farewell. "Good-bye," smiled Rebecca Mary, bravely. And the lips of The Other Little Girl moved as though saying it too. The Other Little Girl smiled. And neither of them knew that just then she was beautiful. Aunt Olivia was trying to meet her own courage test. She had been trying a good many days. Duty--stern, unswerving duty--bade her inspect Rebecca Mary's little cookbook diary. Should she not know--ought she not to know the thoughts that were brewing in the child's mind? How else could she bring her up properly? "Read it," Duty said, "find out. Are you afraid?" "I'm ashamed," groaned Aunt Olivia. "Do you think Rebecca Mary would read my diary?" "Is Rebecca Mary bringing you up?" Aunt Olivia sometimes thought so. The puzzle that she had begun to try to solve when Rebecca Mary's white, death-struck mother had laid her baby in Aunt Olivia's unaccustomed arms was getting a little more difficult every day. Some days Aunt Olivia wondered if she ought to give it up. Oh, this bringing up--this bringing up of little children! "If I must," groaned Aunt Olivia, and got as far as taking the little diary in her hands. But she got no farther. She laid it gently down again. "I can't," she said, firmly, but she could not look Duty in the face as she said it. She had always listened to Duty before. "You know you ought to--" "Yes, I know, but I can't! It seems a shameful thing to do. I'm sure I've tried often enough--you know I've tried--" "I know--that was good practice. Now stop trying and read it!" Aunt Olivia flamed up. "I tell you I won't! It's a shameful thing. If I found Rebecca Mary reading one of my diaries, I should send her to bed--" "Read hers and go to bed yourself. It's your duty to read it. When you bring up a child--" "I never will again!" Aunt Olivia read it, with the relentless grip of Duty holding her to the task. But flame spots crept up through the sallow of her thin cheeks and made what atonement they could. It did not take long, though some of the pages she read twice. The weatherless week, when Rebecca Mary had put off her "asking" from day to day, Aunt Olivia went back to the third time. When she closed the little book it was not a Plummer face she lifted it to and laid it against for the space of a breath--a Plummer face would not have been wet. Then she Whirled upon Duty. "Well, I've done it--I hope you're satisfied!" "It had to be done," calm Duty responded. "If you think it will make you feel any better, you can send yourself to bed." "I'm going to," sighed Aunt Olivia, slipping away to her room. A strange little yearning was upon her to hunt up Rebecca Mary and call her darling and dear. But in her heart she knew she should not have the courage to do it. Here was another Plummer coward! "Why are some people made like me?" she thought--"so it kills 'em to say anything anyways tenderish. Seems to be too much for their vocal organs--they'd rather do a week's washing!" Other thoughts came to Aunt Olivia as she lay on her bed, doing her whimsical penance for violating the sanctity of the little old cookbook. She was not comfortable. It was a hard bed--nothing was soft of Aunt Olivia's. She moved about on it uneasily. "When they're dead, we're willing enough to say tenderish things to 'em," her musings ran. "We wish we HAD then. I suppose if Rebecca Mary was--" She got no farther for the sudden horror that was upon her--that sent her to her feet and to the door. But there she stopped in the blessed relief that drifted in to her on a child's laugh. Somewhere out there Rebecca Mary was laughing in her subdued, sweet way. A cracked, shrill crow followed--Thomas Jefferson was laughing too. Rebecca Mary was not dead. There was time to say a "tenderish" thing to her before she lay--before that. Aunt Olivia shut her eyes resolutely to the vision that had intruded upon her musings. It was Rebecca Mary who was laughing somewhere out there that she wanted to see. The next day was Sunday, and in the quiet of the long afternoon Rebecca Mary read aloud again to Thomas Jefferson. It was from the little cookbook diary. Thomas Jefferson was pecking about the long grass of the orchard. "Oh, listen!" cried Rebecca Mary, her eyes unwontedly shining. "Listen to this, Thomas Jefferson! "'SATURDAY.--Wind northwest by Mrs. Tupper's Weather vain. Something happened yesterday. Aunt Olivia didn't say it, but she most did. She came right out of her bedroom and I saw it in her face! "Dear"--"darling,"--they were both there, and she was looking at me! Nobody EVER looked "dear" "darling" at me before. I suppose my mother would have. If I hadent had another mother I think I should like to have had Aunt Olivia. "'You feel that way more after you get akquainted. When I get VERY akquainted prehaps I shall tell Aunt Olivia. Its quear, I think, how it isent as easy to say some things as it is to think them. You can wright them easier too. I am glad Ime keeping a diary because I can wright about yesterday and what happenned. I shall read it to my grand children--to be continude. "'SUNDAY'--that's today, Thomas Jefferson,--'SUNDAY.--This is yesterday continude, because there was too mutch for one day. Something else beutiful happenned. My Aunt Olivia said to me as folows, I have desided to pay you a weakly alowance of 10 cents a weak Rebecca Mary. And I never asked her to. And she never said anything about charging me for my sins. I was going to ask her but I found out she was poor. That was a mistake, she isent. She must be SOME well of I think for 10 cents seams a great deal to have of your own every weak. But I shant buy crimpers. Ime going to buy a present for Aunt Olivia byamby. Ime very happy. I wish I knew how to spell hooray.'" Suddenly Rebecca Mary was on her feet, waving the cookbook jubilantly. "Hoo-ray! Hoo-ray! Thomas Jefferson!" she shouted, surprising the gentle Sunday calm. She surprised Thomas Jefferson, too, but he was equal to the occasion--Thomas Jefferson was a gentleman. "Hoo-ra-a-a-ay!" he crowed, splendidly, with a fine effect of clapping his hands. This time there could be no doubt. This was applause. The Bereavement Thomas Jefferson was losing his appetite. Even Aunt Olivia noticed it, but it did not worry her as it did Rebecca Mary. "He's always had as many appetites as a cat's got lives--he's got eight good ones left," she said, calmly. But Rebecca Mary was not calm. It seemed to her that Thomas Jefferson was getting thinner every day. "Oh, I can feel your bones!" she cried, in distress. "Your bones are coming through, you poor, dear Thomas Jefferson! Won't you eat just one more kernel of corn--just this one for Rebecca Mary? I'd do it for you. Shut your eyes and swallow it right down and you'll never know it." That day Thomas Jefferson listened to pleading, but not the next day--nor the next. He went about dispiritedly, and the last few times that he crowed it made Rebecca Mary cry. Even Aunt Olivia shook her head. "I could do it better than that myself," she said, soberly. Rebecca Mary hunted bugs and angleworms and arranged them temptingly in rows, but the big, white rooster passed them by with a feeble peck or two. Bits of bread failed to tempt him, or even his favorite cooky crumbs. His eighth appetite departed--his seventh, sixth, fifth, fourth. "He lost his third one yesterday," lamented Rebecca Mary, "and today he's lost his second. It's pretty bad when he hasn't only one left, Aunt Olivia." "Pretty bad," nodded Aunt Olivia. She was stirring up a warm mush. When Rebecca Mary had gone upstairs she took it to Thomas Jefferson and commanded him to eat. He was beyond coaxing--perhaps he needed commanding. Rebecca Mary thought Aunt Olivia did not care, and it added a new sting to her pain. There was that time that Aunt Olivia said she wished the Lord hadn't ever created roosters--Thomas Jefferson had just scratched up her <DW29> seeds. And the time when she wished Thomas Jefferson was dead; did she wish that now? Was she--was she glad he was going to be dead? For Rebecca Mary had given up hope. She was not reconciled, but she was sure. She spent all her spare time with the big, gaunt, pitiful fellow, trying to make his last days easier. She knew he liked to have her with him. "You do, don't you, dear?" she said. She had never called him "dear" before. She realized sadly that this was her last chance. "You do like to have me here, don't you? You'd rather? Don't try to crow--just nod your head a little if you do." And the big, white fellow's head had nodded a little, she was sure. She put out her loving little brown hand and caressed it. "I knew you did, dear. Oh, Thomas Jefferson, Thomas Jefferson, don't die! PLEASE don't--think of the good times we'll have if you won't! Think of the--the grasshoppers--the bugs, Thomas Jefferson--the cookies! Won't you think?--won't you try to be a little bit hungry?" Rebecca Mary knew what it was to be hungry and not be able to eat, but to be able to eat and not be hungry--this was away and beyond her experience. The sad puzzle of it she could not solve. One day the minister had a rather surprising summons to perform his priestly functions. The summoner was Rebecca Mary. She appeared like a sombre little shadow in his sunny sermon room. The minister's wife ushered her in, and in the brief instant of opening the door and announcing her name flashed him a warning glance. He had been acquainted so long with her glances that he was able to interpret this one with considerable accuracy. "All right," he glanced back. No, he would not smile--yes, he would remember that it was Rebecca Mary. "Do what she asks you," flashed the minister's wife's glance. "All right," flashed the minister. Then the door closed. "Thomas Jefferson is dying," Rebecca Mary began, hurriedly. "I came to see if you'd come." In spite of himself the minister gasped. Then, as the situation dawned clearly upon him, his mouth corners began--in spite of themselves--to curve upward. But in time he remembered the minister's wife, and drew them back to their centres of gravity. He waited a little. It was safer. "Aunt Olivia isn't at home and I'm glad. She doesn't care. Perhaps she would laugh. Oh, I know," appealed Rebecca Mary, piteously, "I know he's a rooster! It isn't because I don't know--but he's FOLKS to me! You needn't do anything but just smooth his feathers a little and say the Lord bless you. I thought perhaps you'd come and do that. _I_ could, but I wanted you to, because you're a minister. I thought--I thought perhaps you'd try and forget he's a rooster." "I will," the minister said, gently. Now his lips were quite grave. He took Rebecca Mary's hand and went with her. "He's a good man," murmured the minister's wife, watching them go. She had known he would go. "He was one of my parishioners," the minister was saying for the comforting of Rebecca Mary. Unconsciously he used the past tense, as one speaks of those close to death. It was well enough, for already big, gaunt, white Thomas Jefferson was in the past tense. Rebecca Mary chronicled the sad event in her diary: "Tomas Jefferson passed away at ten minutes of three this afternoon blessed are them that die in the Lord. The minnister did not get here in time. I wish I had asked him to run for he is a very good minnister and would have. He helped me berry him in the cold cold ground and we sang a him. I dident ask him to pray because he was only a rooster, but he was folks to me. I loved him. It is very lonesome. I dred wakening up tomorrow because he always crowed under my window. The Lord gaveth and the Lord has taken away." This last Rebecca Mary erased once, but she wrote it again after a moment's thought. For, she reasoned, it was the Lord part of Aunt Olivia which had given Thomas Jefferson to her. In the primitive little creed of Rebecca Mary every one had a Lord part, but some people's was very small. Not Aunt Olivia's--she had never gauged Aunt Olivia's Lord part; it would not have been consistent with her ideas of loyalty. It was very lonely, as Rebecca Mary had known it would be. At best her life had never been overfull of companionships, and the sudden taking-off--it seemed sudden, as all deaths do--of Thomas Jefferson was hard to bear. Strange how blank a space one great, white rooster can leave behind him! The yard and the orchard seemed full of blank spaces, though in a way Thomas Jefferson's soul seemed to frequent his old beloved haunts. Rebecca Mary could not see it pecking daintily about, but she felt it was there. "His soul isn't dead," she persisted, gently. She clung to the comfort of that. And one morning she thought she heard again Thomas Jefferson's old, cheery greeting to the sunrise. The sound she thought she heard woke her instantly. Was it Thomas Jefferson's soul crowing? "Aunt Olivia isent sorry," chronicled the diary, sadly. "Prehaps shes glad. Once she wished the Lord had forgot to create roosters. But she was ever kind to Tomas Jefferson, considdering the seeds he scrached up. That was his besittingest sin and I know he is sorry now. I wish Aunt Olivia was sorry." Nothing was ever said between the two about Rebecca Mary's loss, but Aunt Olivia recognized the keenness of it to the child. She worried a little about it; it reminded her of that other time of worry when Rebecca Mary and she had nearly starved. Sheets and roosters--there were so many worries in the world. That other time she went to the minister, this time to the minister's wife. One afternoon she went and carried her work. "You know about children," she began, without loss of time. "What happens when they lose their appetite over a dead rooster?" "Thomas Jefferson?" breathed the minister's wife, softly. "Yes--he's dead and buried, and she's mourning for him. I set three tarts on for dinner today, and I set three tarts AWAY after dinner. Rebecca Mary is fond of tarts. What should you do if it was Rhoda?" "Oh---Rhoda--why, I think I should get her another rooster, or a cat or something, to get her mind off. But Rhoda isn't Rebecca Mary--" Aunt Olivia folded up her work. She got up briskly. "They've got a white rooster down to the Trumbullses'," she said. "I guess I better go right down now; Tony Trumbull is liable to be at home just before supper. I'm very much obliged to you for your advice." "Did I advise her?" murmured the minister's wife, watching the resolute swing of Aunt Olivia's skirts as she strode away. "I was going to tell her that what would cure my Rhoda might not cure Rebecca Mary. Well, I hope it will work," but she was sure it wouldn't. She had grown a little acquainted with Rebecca Mary. It was the new, white rooster crowing, instead of the soul of Thomas Jefferson. Rebecca Mary found out after she had dressed and gone downstairs. Soon after that she appeared in the kitchen doorway with an armful of snowy feathers. Aunt Olivia, over her muffin pans, eyed her with secret delight. The cure was working sooner than she had dared to expect. "This is the Tony Trumbullses' rooster; if I hurry I guess I can carry him back before breakfast," Rebecca Mary said from the doorway. "I'll run, Aunt Olivia." "Carry him back!" Aunt Olivia's muffin spoon dropped into the bowl of creamy batter. One look at Rebecca Mary convinced her that the cure had not begun to work. Imperceptibly she stiffened. "He ain't anybody's but mine. I've bought him," she explained, briefly. "You set him down and feed him with these crumbs--he ain't human if he don't like cloth-o'-gold cake." But the child in the doorway, after gently releasing the great fellow, drew away quietly. The second look at her face convinced Aunt Olivia that the cure would never work. "You feed him, please, Aunt Olivia," Rebecca Mary said; "I--couldn't. I'll stir the muffins up." Nothing further was ever said about keeping the Tony Trumbull rooster. He pecked about the place in unrestrained freedom until the morning work was done, and then Aunt Olivia carried him home in her apron. "I concluded not to keep him--he'd likely be homesick," she said, with a qualm of conscience; for the big, white fellow had certainly shown no signs of homesickness. But she could not explain and reveal the secret places of Rebecca Mary's heart. Aunt Olivia, too, had her ideas of loyalty. In the diary there occurred brief mention of the episode: "The Tony Trumbull rooster has been here. I could eat him--that's how I feel about the Tony Trumbull rooster. "I never could have eatten Tomas Jefferson but once and then it would have broken my heart but I was starveing. Aunt Olivia took him back." Thomas Jefferson's grave was kept green. Rebecca Mary took her stents down into the orchard and sat beside it, sadly stitching. She kept it heaped with wild flowers and poppies from her own rows. Aunt Olivia's flowers she never touched. The bitterness of Aunt Olivia's not being sorry--perhaps being glad--rankled in her sore little soul. It would have helped--oh yes, it would have helped. Aunt Olivia worried on. It seemed to her that all Rebecca Mary's meals in one meal would not have kept a kitten alive--and that reminded her. She would try a kitten. The minister's wife had said a rooster or a cat. A white kitten, she decided, though she could scarcely have told why. The kitten was better, but it was not a cure. Rebecca Mary took the little creature to her breast and told it her grief for Thomas Jefferson and cried her Thomas Jefferson tears into its soft, white fur. In that way, at any rate, it was a success. "Maybe I shall love you some day," she whispered, "but I can't yet, while Thomas Jefferson is fresh. He's all I have room for. He was my intimate friend--when your intimate friend is dead you can't love anybody else right away." But she apologized to the little cat gently--she felt that an apology was due it. "You see how it is, little, white cat," she said. "I shall have to ask you to wait. But if I ever have a second love, I promise it will be you. You're a great DEAL comfortinger than that Tony Trumbull rooster! I could love you this minute if I had never loved Thomas Jefferson. Do you feel like waiting?" The little, white cat waited. And Aunt Olivia waited. She made tempting dishes for Rebecca Mary's meals, and put a ruffle into her nightgown neck and sleeves--Rebecca Mary had always yearned for ruffles. "I don't believe she sees 'em. She don't know they're there," groaned Aunt Olivia, impotently. "She don't see anything but Thomas Jefferson, and I don't know as she ever will!" But Rebecca Mary saw the ruffles and fluted them between her brown little fingers admiringly. She tried once or twice to go and thank Aunt Olivia, and got as far as her bedroom door. But the bitterness in her heart stayed her hand from turning the knob. If Aunt Olivia had only known that being sorry was the right thing to do! Strangely enough, though Rebecca Mary's view of the matter never occurred to Aunt Olivia, she came by and by to being sorry on her own account. Perhaps she had been all along, underneath her disquietude for Rebecca Mary's sorrow. Perhaps when she thought how quiet it had grown mornings, and what a good chance there was now for a supplementary nap, she was being sorry. When she remembered that she need not buy wheat now and yellow corn, and that the cookies would last longer--perhaps then she was sorry. But she did not know it. It seemed to come upon her with the nature of a surprise on one especial day. She had been working her un-"scrached," untrampled flower-beds. "My grief!" she ejaculated, suddenly, as if just aware of it. "I declare I believe I miss him, too! I believe to my soul I'd like to hear him crow--I wouldn't mind if he came strutting in here!" And "in here" was Aunt Olivia's beloved garden of flowers. Surely she was being sorry now! It was the next day that Rebecca Mary's bitterness was sweetened--that she began to be cured. She and the little, white cat went down together to Thomas Jefferson's resting place. When they went home--and they went soon--Rebecca Mary got her diary and began to write in it with eager haste. Her sombre little face had lighted up with some inner gladness, like relief: "Shes been there and put some lavvender on and pinks. I mean Aunt Olivia. And shes the very fondest of her pinks and lavvender. So she must have loved Tomas Jefferson. Shes sorry. Shes sorry. Shes sorry. And Ime so glad." Rebecca Mary caught up the little, white cat and cried her first tear of joy on its neck. Then she wrote again: "Now there are two morners instead of one. Two morners seams so mutch lovinger than only one. I know he must feal better. I think he must have been hurt before and so was I. I wish I dass tell Aunt Olivia how glad I am shes sorry." But she told only the little, white cat. The Plummer mantle of reticence had fallen too heavily on her narrow little shoulders. What she longed to do she did not "dass." But that evening in her little ruffled nightgown she went to Aunt Olivia's room and thanked her for the ruffles. "They're beautiful," she murmured, in a small agony of shyness. "I think it was very kind of you to ruffle me--I've always wanted to be. Thank you very much." And then she had scurried away on her bare feet to the safe retreat of her own room under the eaves. Aunt Olivia, left behind, was unconsciously relieved at not having to respond. She was glad the child had discovered the ruffles and was pleased. It was a good sign. "I'll mix up some pancakes in the morning," Aunt Olivia said, complacently. "Pancakes may help along. Rebecca Mary is fond of 'em." The pinks and the fragrant lavender appeared to have established a certain unspoken comradeship between the two "morners" of Thomas Jefferson. Thereafter Rebecca Mary went about comforted, and Aunt Olivia relieved. The little, white cat purred about the skirts of one and the stubbed-out toes of the other in cheerful content. "Well?" the minister's wife queried, in a moment of social intercourse after church. She and Aunt Olivia walked down the aisle together. "She's getting over it--or beginning to," nodded Aunt Olivia. "That other rooster didn't work, but I think the little cat is going to. She hugs it." "Good! But she still mourns Thomas Jef--" "Of course!" Aunt Olivia interposed, rather crisply. "You couldn't expect her to get over it all in a minute. He was a remarkable rooster." "She misses him, herself," inwardly smiled the minister's little wife. Whether by virtue of her relationship to the minister or by her own virtue, she had learned to read human nature with a degree of accuracy. "I looked at myself in the glass tonight," confessed Rebecca Mary's diary, "but it was on acount of the rufles. I think Ime not quite so homebly in rufles. I think Aunt Olivia was kind to rufle me. I should like to ware this night gown in the day time. I wish folks did." The pencil slipped out of Rebecca Mary's fingers and rolled on the floor, to the undoing of the little, white cat, who had gone to bed in his basket. Rebecca Mary caught him up as he darted after the pencil, and hugged him in an odd little ecstasy. She felt oddly happy. "You little, white cat!" she cried, muffledly, her face in his thick coat, "you've waited and waited, but I think I'm going to love you now--you needn't wait any more." The Feel Doll The minister uttered a suppressed note of warning as solid little steps sounded in the hall. It was he who threw a hasty covering over the doll. The minister's wife sewed on undisturbedly. She did worse than that. "Come here, Rhoda," she called, "and tell me which you like better, three tucks or five in this petticoat?" "Five," promptly, upon inspection. Rhoda pulled away the concealing cover and regarded the stolid doll with tilted head. "She's 'nough like my Pharaoh's Daughter to be a blood relation," she remarked. "She's got the Pharaoh complexion." "Spoken like MY daughter!" laughed the minister. "But I thought new dolls in this house were always surprises. And here's Mrs. Minister making doll petticoats out in the open!" "This is Rebecca Mary's--I'm dressing a doll for Rebecca Mary, Robert. She's eleven years old and never had a doll! Rhoda's ten and has had--How many dolls have you had, Rhoda?" "Gracious! Why, Pharaoh's Daughter, an' Caiapha, an' Esther the Beautiful Queen, an' the Children of Israel--five o' them--an' Mrs. Job, an'--" "Never mind the rest, dear. You hear, Robert? Do you think Rhoda would be alive now if she'd never had a doll?" The minister pondered the question. "Maybe not, maybe not," he decided; "but possibly the dolls would have been." "Don't make me smile, Robert. I'm trying to make you cry. If Rebecca Mary were sixty instead of eleven I should dress her a doll." "Then why not one for Miss Olivia?" "I may dress her one," undauntedly, "if I find out she never had one in her life." "She never did." The minister's voice was positive. "And for that reason, dear, aren't you afraid she would not approve of Rebecca Mary's having one? Isn't it rather a delicate mat--" "Don't, Robert, don't discourage me. It's going to be such a beautiful doll! And you needn't tell me that poor little eleven-year-old woman-child won't hold out her empty arms for it. Robert, you're a minister; would it be wrong to give it to her STRAIGHT?" "Straight, dear?" "Yes; without saying anything to her aunt Olivia. Tell me. Rhoda's gone. Say it as--as liberally as you can." The minister for answer swept doll, petticoat, and minister's wife into his arms, and kissed them all impartially. "Think if it were Rhoda," she pleaded. "And you were 'Aunt Olivia'? You ask me to think such hard things, dear! If I could stop being a minister long enough--" "Stop?" she laughed; but she knew she meant keep on. With a sigh she burrowed a little deeper in his neck. "Then I'll ask Aunt Olivia first," she said. She went back to her tucking. Only once more did she mention Rebecca Mary. The once was after she had come downstairs from tucking the children into bed. She stood in the doorway with the look in her face that mothers have after doing things like that. The minister loved that look. "Robert, nights when I kiss the children--you knew when you married me that I was foolish--I kiss little lone Rebecca Mary, too. I began the day Thomas Jefferson died--I went to the Rebecca-Mary-est window and threw her a kiss. I went tonight. Don't say a word; you knew when you married me." Aunt Olivia received the resplendent doll in silence. Plummer honesty and Plummer politeness were at variance. Plummer politeness said: "Thank her. For goodness' sake, aren't you going to thank the minister's wife?" But Plummer honesty, grim and yieldless, said, "You can't thank her, because you're not thankful." So Aunt Olivia sat silent, with her resplendent doll across her knees. "For Rebecca Mary," the minister's wife was saying, in rather a halting way. "I dressed it for her. I thought perhaps she never--" "She never," said Aunt Olivia, briefly. Strange that at that particular instant she should remember a trifling incident in the child's far-off childhood. The incident had to do with a little, white nightgown rolled tightly and pinned together. She had found Rebecca Mary in her little waist and petticoat cuddling it in bed. "It's a dollie. Please 'sh, Aunt Olivia, or you'll wake her up!" the child had whispered, in an agony. "Oh, you're not agoing to turn her back to a nightgown? Don't unpin her, Aunt Olivia--it will kill her! I'll name her after you if you'll let her stay." "Get up and take your clothes off." Strange Aunt Olivia should remember at this particular instant; should remember, too, that the pin had been a little rusty and came out hard. Rebecca Mary had slid out of bed obediently, but there had been a look on her little brown face as of one bereaved. She had watched the pin come out, and the nightgown unroll, in stricken silence. When it hung released and limp over Aunt Olivia's arm she had given one little cry: "She's dead!" The minister's wife was talking hurriedly. Her voice seemed a good way off; it had the effect of coming nearer and growing louder as Aunt Olivia stepped back across the years. "Of course you are to do as you think best about giving it to her," the minister's wife said, unwillingly. This came of being a minister's wife! "But I think--I have always thought--that little girls ought--I mean Rhoda ought--to have dolls to cuddle. It seems part of their--her--inheritance." This was hard work! If Miss Olivia would not sit there looking like that--. "As if I'd done something unkind!" thought the gentle little mother, indignantly. She got up presently and went away. But Aunt Olivia, with the doll hanging unhealthily over her arm, followed her to the door. There was something the Plummer honesty insisted upon Aunt Olivia's saying. She said it reluctantly: "I think I ought to tell you that I've never believed in dolls. I've always thought they were a waste of time and kept children from learning to do useful things. I've brought Rebecca Mary up according to my best light." "Worst darkness!" thought the minister's wife, hotly. "She's never had a doll. I never had one. I got along. I could make butter when I was seven. So perhaps you'd better take the doll--" "No, no! Please keep it, Miss Olivia, and if you should ever change your mind--I mean perhaps sometime--good-bye. It's a beautiful day, isn't it?" Aunt Olivia took it up into the guest chamber and laid it in an empty bureau drawer. She closed the drawer hastily. She did not feel as duty-proof as she had once felt, before things had happened--softening things that had pulled at her heartstrings and weakened her. The quilt on the guest chamber bed was one of the things; she would not look at it now. And the sheets under the quilt--and the grave of Thomas Jefferson that she could see from the guest chamber window. Aunt Olivia was terribly beset with the temptation to take the doll out to Rebecca Mary in the garden. "Are you going to do it?" demanded Duty, confronting her. "Are you going to give up all your convictions now? Rebecca Mary's in her twelfth year-pretty late to begin to humor her. I thought you didn't believe in humoring." "I unpinned the nightgown," parried Aunt Olivia, on the defensive. "I never let her make another one." "But you're weakening now. You want to let her have THIS doll." "It seems like part of--of her inheritance." "Lock that drawer!" Aunt Olivia turned the key unhappily. It was not that her "convictions" had changed--it was her heart. She went up at odd times and looked at the doll the minister's wife had dressed. She had an unaccountable, uncomfortable feeling that it was lying there in its coffin--that Rebecca Mary would have said, "She's dead." It was a handsome doll. Aunt Olivia was not acquainted with dolls, but she acknowledged that. She admired it unwillingly. She liked its clothes--the minister's wife had not spared any pains. She had not stinted in tucks nor ruffles. Once Aunt Olivia took it out and turned it over in her hands with critical intent, but there was nothing to criticise. It was a beautiful doll. She held it with a curious, shy tenderness. But that time she did not sit down with it. It was the next time. The rocker was so near the bureau, and Aunt Olivia was tired--and the doll was already in her arms. She only sat down. For a minute she sat quite straight and unrelaxed, then she settled back a little--a little more. The doll lay heavily against her, its flaxen head touching her breast. After the manner of high-bred dolls, its eyes drooped sleepily. Aunt Olivia began to rock--a gentle sway back and forth. She was sixty, but this was the first time she had ever rocked a chi--a doll. So she rocked for a little, scarcely knowing it. When she found out, a wave of soft pink dyed her face and flowed upward redly to her hair. "Well!" Duty jibed, mocking her. "Don't say a word!" cried poor Aunt Olivia. "I'll put her right back." "What good will that do?" "I'll lock her in." "You've locked her in before." "I'll--I'll hide the key." "Where you can find it! Think again." Aunt Olivia thrust the doll back into its coffin with unsteady hands. The red in her face had faded to a faint, abiding pink. She locked the drawer and drew out the key. She strode to the window and flung it out with a wide sweep of her arm. The minister's wife, ignorant of the results of her kind little experiment, resolved to question Rebecca Mary the next time she came on an errand. She would do it with extreme caution. "I'll just feel round," she said. "I want to know if her aunt's given it to her. You think she must have, don't you, Robert? By this time? Why, it was six weeks ago I carried it over! It was such a nice, friendly little doll! By this time they would be such friends--if her aunt gave it to her. Robert, you think--" "I think it's going to rain," the minister said. But he kissed her to make it easier. Rebecca Mary came over to bring Aunt Olivia's rule for parson-cake that the minister's wife had asked for. "Come in, Rebecca Mary," the minister's wife said, cordially. "Don't you want to see the new dress Rhoda's doll is going to have? I suppose you could make your doll's dress yourself?" It seemed a hard thing to say. Feeling round was not pleasant. "P'haps I could, but she doesn't wear dresses," Rebecca Mary answered, gravely. "No?" This was puzzling. "Her clothes don't come off, I suppose?" Then it could not be the nice, friendly doll. "No'm. Nor they don't go on, either. She isn't a feel doll." "A--what kind did you say, dear?" The minister's wife paused in her work interestedly. Distinctly, Miss Olivia had not given her THE doll; but this doll--"I don't think I quite understood, Rebecca Mary." "No'm; it's a little hard. She isn't a FEEL doll, I said. I never had a feel one. Mine hasn't any body, just a soul. But she's a great comfort." "Robert," appealed the minister's wife, helplessly. This was a case for the minister--a case of souls. "Tell us some more about her, Rebecca Mary," the minister urged, gently. But there was helplessness, too, in his eyes. "Why, that's all!" returned Rebecca Mary, in surprise. "Of course I can't dress her or undress her or take her out calling. But it's a great comfort to rock her soul to sleep." "Call Rhoda," murmured the wife to the minister; but Rhoda was already there. She volunteered prompt explanation. There was no hesitation in Rhoda's face. "She means a make believe doll. Don't you, Rebecca Mary?" "Yes," Rebecca Mary assented; "that's her other name, I suppose, but I never called her by it." "What did you call her?" demanded practical Rhoda. "What's her name mean?" "Rhoda!"--hastily, from the minister's wife. This seemed like sacrilege. But Rhoda's clear, blue eyes were fixed upon Rebecca Mary; she had not heard her mother's warning little word. A shy color spread thinly over the lean little face of Rebecca Mary. For the space of a breath or two she hesitated. "Her name's--Felicia," then, softly. "Robert"--the children had gone out together; the minister's wife's eyes were unashamedly wet--"Robert, I wish you were a--a sheriff instead of a minister. Because I think I would make a better sheriff's wife. Do you know what I would make you do?" The minister could guess. "I'd make you ARREST that woman, Robert!" "Felicia!" But she saw willingness to be a sheriff come into his own eyes and stop there briefly. "Don't call me 'Felicia' while I feel as wicked as this! Oh, Robert, to think she named her little soul-doll after me!" "It's a beautiful name." Suddenly the wickedness was over. She laughed unsteadily. "It wouldn't be a good name for a sheriff's wife, would it?" she said. "So I'll stay by my own minister." One day close upon this time Aunt Olivia came abruptly upon Rebecca Mary in the grape arbor. She was sitting in her little rocking chair, swaying back and forth slowly. She did not see Aunt Olivia. What was she was crooning half under her breath? "Oh, hush, oh, hush, my dollie; Don't worry any more, For Rebecca Mary 'n' the angels Are watching o'er, ---O'er 'n' o'er 'n' o'er." The same words over and over--growing perhaps a little softer and tenderer. Rebecca Mary's arm was crooked as though a little flaxen head lay in the bend of it. Rebecca Mary's brooding little face was gazing downward intently at her empty arm. Quite suddenly it came upon Aunt Olivia that she had seen the child rocking like this before--that she must have seen her often. "Rebecca Mary 'n' the angels Are watching o'er," sang on the crooning little voice in Aunt Olivia's ears. The doll in its coffin upstairs; down here Rebecca Mary rocking her empty arms. The two thoughts flashed into Aunt Olivia's mind and welded into one. All her vacillations and Duty's sharp reminders occurred to her clearly. She had thought that at last she was proof against temptation, but she had not thought of this. She was not prepared for Rebecca Mary, here in her little rocking chair, rocking her little soul-doll to sleep. The angels were used to watching o'er, but Aunt Olivia could not bear it. She went away with a strange, unaccustomed ache in her throat. The minister's wife would not have wanted her arrested then. Aunt Olivia tiptoed away as though Rebecca Mary had said, "'Sh!" She was remembering, as she went, the brief, sweet moment when she had sat like that and rocked, with the doll the minister's wife dressed, in her arms. It seemed to establish a new link of kinship between her and Rebecca Mary. She ran plump into Duty. "Oh!" she gasped. She was a little stunned. Aunt Olivia's Duty was solid. "I know where you've been. I tried get there in time." "You're too late," Aunt Olivia said, firmly, "Don't stop me; there's something I must do before it gets too dark. It's six o'clock now." "Wait!" commanded Duty. "Are you crazy? You don't mean--" "Go back there and look at that child--and hear what she's singing! Stay long enough to take it all in--don't hurry." But Duty barred her way, grim and stern. Palely she put up both her hands and thrust it aside. She did not once look back at it. Already it was dusky under the guest chamber window. She had to stoop and peer and feel in the long tangle of grass. She kept on patiently with the Plummer kind of patience that never gave up. She was eager and smiling, as though something pleasant were at the end of the peering and stooping and feeling. Aunt Olivia was hunting for a key. The Plummer Kind The doll's name was Olivicia. Rebecca Mary had evolved the name from her inner consciousness and her intense gratitude to Aunt Olivia and the minister's wife. She had put Aunt Olivia first with instinctive loyalty, though in the secret little closet of her soul she had longed to call the beautiful being Felicia, intact and sweet. She did not know the meaning of Felicia, but she knew that the doll, as it lay in the loving cradle of her arms, gazing upward with changeless placidity and graciousness, looked as one should look whose name was Felicia. Greater compliment than this Rebecca Mary could not have paid the minister's wife. "Olivicia," she had placed the being on the sill of the attic window, stood confronting, addressing it: "Olivicia, it's coming--it is very near to! Sit there and listen and smile--oh yes, smile, SMILE. I don't wonder! I would too, only I'm too glad. When you're TOO glad you can't smile. I've been waiting for it to come. Olivicia, seems as if I'd been waiting a thousan' years. You're so young, you've only lived such little while, of course I don't expect you understand the deep-downness inside o' me when I think--" The address fluttered and came to a standstill here. Rebecca Mary was suddenly minded that Olivicia was in the dark; must be enlightened before she could smile understandingly. "Why, you poor dear!--why, you don't know what it is that's coming and that's near to! It's the--city, Olivicia," enlightened Rebecca Mary, gently, to insure against shock. "Aunt Olivia's going--to--the--city." In Rebecca Mary's dreamings it had always been THE city. It did not need local habitation and a name; enough that it had streets upon streets, houses upon houses upon houses, a dazzling swirl of men, women, and little children--noise, glitter, glory. In her dreamings the city was something so wondrous and grand that Heaven might have been its name. The streets upon streets were not paved with gold, of course--of course she knew they were not paved with gold! But in spite of herself she knew that she would be disappointed if they did not shine. Aunt Olivia had said it that morning. At breakfast--quite matter-of-factly. Think of saying it matter-of-factly! "I'm going to the city soon, Rebecca Mary," she had said, between sips of her tea. "Perhaps by Friday week, but I haven't set the day, really. There's a good deal to do." Rebecca Mary had been helping do it all day. Now it was nearly time for the pageant of red and gold in the west that Rebecca Mary loved, and she had come up here with the beautiful being to watch it through the tiny panes of the attic window, but more to ease the aching rapture in her soul by speech. She must say it out loud. The city--the city--to the city of streets and houses and men and wonders upon wonders! Olivicia had come in the capacity of calm listener; for nothing excited Olivicia. "I," Aunt Olivia had said, but Aunt Olivia usually said "I." There was no discouragement in that to Rebecca Mary. It did not for a moment occur to her that "I" did not mean "we." The valise they had got down from its cobwebby niche was roomy; it would hold enough for two. Rebecca Mary knew that, because she had packed it so many times in her dreamings. She wished Aunt Olivia would let her pack it now. She knew just where she would put everything--her best dress and Aunt Olivia's (for of course they would wear their second-bests), their best hats and shoes and gloves. Their nightgowns she would roll tightly and put in one end, for it doesn't hurt nightgowns to be rolled tightly. Of course she would not put anything heavy, like hair brushes and shoes and things, on top of anything--unless it was the nightgowns, for it doesn't hurt-- "Oh, Olivicia--oh, Olivicia, how I hope she'll say, 'Rebecca Mary, you may pack the valise'! I could do it with my eyes shut, I've done it so many, many times!" But Aunt Olivia did not say it. One day and then another went by without her saying it, and then one morning Rebecca Mary knew by the plump, well-fed aspect of the valise that it was packed. Aunt Olivia had packed it in the night. There was no one else in the room when Rebecca Mary made her disappointing little discovery. She went over to the plump valise and prodded it gently with her finger. But it is so difficult to tell in that way whether your own best dress, your own best hat, best shoes, best gloves, are in there. Rebecca Mary hurried upstairs and looked in her closet and in her "best" bureau drawer. They were not there! In her relief she caught up the beautiful being and strained her hard, lifeless little body to her own warm breast. If she had not been Rebecca Mary, she would have danced about the room. "Oh, I'm so relieved, Olivicia!" she laughed, softly. "If they're not up here, THEY'RE DOWN THERE. They've got to be somewhere. They're in that valise--valise--vali-i-ise!" Rebecca Mary had never been to a city, and within her remembrance Aunt Olivia had never been. Curiosity was not a Plummer trait, hence Rebecca Mary had never asked many questions about the remote period before her own advent into Aunt Olivia's life. The same Plummer restraint kept her now from asking questions. There was nothing to do but wait, but the waiting was illumined by her joyous anticipations. Oddly enough, Aunt Olivia seemed to have no anticipations--at least joyous ones. Her, thin, grave face may even have looked a little thinner and graver, IF Rebecca Mary had thought to notice. The night the lean old valise took on plumpness, Aunt Olivia went often into Mary's little room. Many of the times she came out very shortly with the child's "best" things trailing from her arms, but once or twice she stayed rather long--long enough to stand beside a little white bed and look down on a flushed little face. A pair of wide-open eyes watched her smilingly from the pillows, but they were not Rebecca Mary's eyes, and Olivicia was altogether trustworthy. An odd thing happened--but Olivicia never told. Why should she publish abroad that she had lain there and seen Aunt Olivia bend once--bend twice--over Rebecca Mary and kiss her? Softly, patiently, very wearily, Aunt Olivia went in and out. The things she brought out in her arms she folded carefully and packed, but not in the lank old valise. She put them all with tender painstaking into a quaint little carpetbag. When the work was done she set the bag away out of sight, and went about packing her own things in the old valise. The day before, she had been to see the minister and the minister's wife. She called for them both, and sat down gravely and made her proposition. It was startling only because of the few words it took to make it. Otherwise it was very pleasant, and the minister and the minister's wife received it with nods and smiles. "Of course, Miss Olivia--why, certainly!" smiled and nodded the minister. "Why, it will be delightful--and Rhoda will be so pleased!" nodded and smiled the minister's wife. But after their caller had gone she faced the minister with indignant eyes. "Why did you let her?" she demanded. "Why did you spoil it all by that?" "Because she was Miss Olivia," he answered, gently. "Yes--yes, I suppose so," reluctantly; "but, anyway, you needn't have let her do it in advance. Actually it made me blush, Robert!" The minister rubbed his cheeks tentatively. "Made me, too," he admitted, "but I respect Miss Olivia so much--" The minister's wife tacked abruptly to her other source of indignation. "Why doesn't she TAKE Rebecca Mary? Robert, wait! You know it isn't because--You know better!" "It isn't because, dear--I know better," he hurried, assuringly. The minister was used to her little indignations and loved them for being hers. They were harmless, too, and wont to have a good excuse for being. This one, now--the minister in his heart wondered that Miss Olivia did not take Rebecca Mary. "It would be such a treat. Robert, you think what a treat it would be to Rebecca Mary!" "Still, dear--" "I don't want to be still! I want Rebecca Mary to have that treat!" But she kissed him in token of being willing to drop it there--it was her usual token--and ran away to get a little room ready. There was not a device known to the minister's wife that she did not use to make that room pleasant. "Shall I take your pincushion, Rhoda?" Rhoda had come up to help. "Yes," eagerly, "and I'll write Welcome with the pins." "And the little fan to put on the wall--the pink one?" "Yes, yes; let me spread it out, mamma!" "That's grand. Now if we only had a pink quilt--" "I 'only have' one!" laughed Rhoda, hurrying after it. The whole little room when they left, like the pins in the pincushion, spelled "WELCOME." Aunt Olivia got up earlier than usual one day and went about the house for a survey. The valise and the little carpetbag she carried downstairs and out on to the front steps. Her face was whitened as if by a long night's vigil. When she called Rebecca Mary it was with a voice strained hoarse. The beautiful being Olivicia watched her with intent, unwinking gaze. Could it be Olivicia understood? "Hurry and dress, Rebecca Mary; there's a good deal to do," Aunt Olivia said at the door. She did not go in. "Yes, in your second-best--don't you see I've put it out. You can wear that every day now, till--for a while." Something in the voice startled Rebecca Mary out of her subdued ecstasy and sent her down to breakfast with a nameless fear tugging at her heart. "You're going to stay at the minister's--I've paid your board in advance," Aunt Olivia said, monotonously, as if it were her lesson. She did not look at Rebecca Mary. "I've put in your long-sleeve aprons so you can help do up the dishes. There's plenty of handkerchiefs to last. You mustn't forget your rubbers when it's wet, or to make up your bed yourself. I don't want you to make the minister's wife any more trouble than you can help." The lesson went monotonously on, but Rebecca Mary scarcely heard. She had heard the first sentence--her sentence, poor child! "You're going to stay at the minister's--stay at the minister's--stay at the minister's." It said itself over and over again in her ears. In her need for somebody to lean on, her startled gaze sought the beautiful being across the room in agonized appeal. But Olivicia was staring smilingly at Aunt Olivia. ET TU, OLIVICIA! If Rebecca Mary had noticed, there was an appealing, wistful look in Aunt Olivia's eyes too, in odd contrast to the firm lips that moved steadily on with their lesson: "You can walk to school with Rhoda, you'll enjoy that. You've never had folks to walk with. And you can stay with her, only you mustn't forget your stents. I've put in some towels to hem. Maybe the minister's wife has got something; if so, hem hers first. You'll be like one o' the family, and they're nice folks, but I want you to keep right on being a Plummer." Years afterwards Rebecca Mary remembered the dizzy dance of the bottles in the caster--they seemed to join hands and sway and swing about their silver circlet and how Aunt Olivia's buttons marched and countermarched up and down Aunt Olivia's alpaca dress. She did not look above the buttons--she did not dare to. If she was to keep right on being a Plummer, she must not cry. "That's all," she heard through the daze and dizziness, "except that I can't tell when I'll be back. It--ain't decided. Likely I shan't be able--there won't be much chance to write, and you needn't expect me to. No need to write me either. That's all, I guess." The stage that came for Aunt Olivia dropped the little carpetbag and Rebecca Mary at the minister's. In the brief interval between the start and the dropping, Rebecca Mary sat, stiff and numb, on the edge of the high seat and gazed out unfamiliarly at the familiar landmarks they lurched past. At any other time the knowledge that she was going to the minister's to stay--to live--would have filled her with staid joy. At any other time--but THIS time only a dull ache filled her little dreary world. Everything seemed to ache--the munching cows in the Trumbull pasture, the cats on the doorsteps, the dog loping along beside the stage, the stage driver's stooping old back. Aunt Olivia was going to the city--Rebecca Mary wasn't going to the city. There was no room in the world for anything but that and the ache. Rebecca Mary's indignation was not born till night. Then, lying in the dainty bed under Rhoda's pink quilt, her mood changed. Until then she had only been disappointed. But then she sat up suddenly and said bitter things about Aunt Olivia. "She's gone to have a good time all to herself--and she might have taken me. She didn't, she didn't, and she might've. She wanted all the good time herself! She didn't want me to have any!" "Rebecca Mary!--did you speak, dear?" It was the gentle voice of the minister's wife outside the door. Rebecca Mary's red little hands unwrung and dropped on the pink quilt. "No'm, I did--I mean yes'm, I didn't--I mean--" "You don't feel sick? There isn't anything the matter, dear?" "No'm--oh, yes'm, yes'm!" for there was something the matter. It was Aunt Olivia. But she must not say it--must not cry--must keep right on being a Plummer. "Robert, I didn't go in--I couldn't," the minister's wife said, back in the cheery sitting room. "I suppose you think I'd have gone in and comforted her, taken her right in my arms and comforted her the Rhoda way, but I didn't." "No?" The minister's voice was a little vague on account of the sermon on his knees. "I seemed to know--something told me right through that door--that she'd rather I wouldn't. Robert, if the child is homesick, it's a different kind of homesickness." "The Plummer kind," he suggested. The minister was coming to. "Yes, the Plummer kind, I suppose, Plummers are such--such PLUMMERY persons, Robert!" Upstairs under the pink quilt the rigid little figure relaxed just enough to admit of getting out of bed and fumbling in the little carpetbag. With her diary in her hand--for Aunt Olivia had remembered her diary--Rebecca Mary went to the window and sat down. She had to hold the cookbook up at a painful angle and peer at it sharply, for the moonlight that filtered into the little room through the vines was dim and soft. "Aunt Olivia has gone to the city and I haven't," painfully traced Rebecca Mary. "She wanted the good time all to herself. I shall never forgive Aunt Olivia the Lord have mercy on her." Then Rebecca Mary went back to bed. She dreamed that the cars ran off the track and they brought Aunt Olivia's pieces home to her. In the dreadful dream she forgave Aunt Olivia. It was very pleasant at the minister's and the minister's wife's. Rebecca Mary felt the warmth and pleasantness of it in every fibre of her body and soul. But she was not happy nor warm. She thought it was indignation against Aunt Olivia--she did not know she was homesick. She did not know why she went to the old home every day after school and wandered through Aunt Olivia's flower garden, and sat with little brown chin palm-deep on the doorsteps. Gradually the indignation melted out of existence and only the homesickness was left. It sat on her small, lean face like a little spectre. It troubled the minister's wife. "What can we do, Robert?" she asked. "What?" he echoed; for the minister, too, was troubled. "She wanders about like a little lost soul. When she plays with the children it's only the outside of her that plays." "Only the outside," he nodded. "Last night I went in, Robert, and--and tried the Rhoda way. I think she liked it, but it didn't comfort her. I am sure now that it is homesickness, Robert." They were both sure, but the grim little spectre sat on, undaunted by all their kindnesses. "When thy father and thy mother forsake the," wrote Rebecca Mary in the cookbook diary, "and thy Aunt Olivia for I know it means and thy Aunt Olivia then the Lord will take the up, but I dont feal as if anyboddy had taken me up. The ministers wife did once but of course she had to put me down again rite away. She is a beutiful person and I love her but she is differunt from thy father and thy mother and thy Aunt Olivia. Ide rather have Aunt Olivia take me up than to have the Lord." It was when she shut the battered little book this time that Rebecca Mary remembered one or two things that had happened the morning Aunt Olivia went away. It was queer how she HADN'T remembered them before. She remembered that Aunt Olivia had taken her sharp little face between her own hands and looked down wistfully at it--wistfully, Rebecca Mary remembered now, though she did not call it by that name. She remembered Aunt Olivia had said, "You needn't hem anything unless it's for the minister's wife--never mind the towels I put in." That was almost the last thing she had said. She had put her head out of the stage door to say it. Rebecca Mary had hemmed a towel each day. There were but two left, and she resolved to hem both of those tomorrow. A sudden little longing was born within her for more towels to hem for Aunt Olivia. It was nearly three weeks after Rebecca Mary's entrance into the minister's family when the letter came. It was directed to Rebecca Mary, and lay on her plate when she came home from school. "Oh, look, you've got a letter, Rebecca Mary!" heralded Rhoda, joyfully. Then her face fell, for maybe the letter would say Aunt Olivia was coming home. "Is it from your aunt Olivia?" she asked, anxiously. "No," Rebecca Mary said, in slow surprise. "The writing isn't, anyway, and the name is another one--" "Oh! Oh! Maybe she's got mar--" "Rhoda!" cautioned the minister. This is the letter Rebecca Mary read: "Dear Rebecca Mary,--You see I know your name from your aunt. She talked about you all the time, but I am writing you of my own accord. She does not know it. I think you will like to know that at last we are feeling very hopeful about your aunt. We have been very anxious since the operation, she had so little strength to rally with. But now if she keeps on as well as this you will have her home again in a little while. The doctors say three weeks. She is the patientest patient in the ward. Yours very truly, Sara Ellen Nesbitt, Nurse" Ward A, Emmons Hospital That was the letter. Rebecca Mary's face grew a little whiter at every line of it. At every line understanding grew clearer, till at the end she knew it all. She gave a little cry, and ran out of the room. Love and remorse and sympathy fought for first place in her laboring little breast. In the next few minutes she lived so long a time and thought so many thoughts! But above everything else towered joy that Aunt Olivia was coming home. Rebecca Mary's eyes blazed with pride at being a Plummer. This kind of courage was the Plummer kind. The child's lank little figure seemed to grow taller and straighter. She held up her head splendidly and exulted. She felt like going up on the minister's housetop and proclaiming: "She's my aunt Olivia! She's mine! She's mine--I'm a Plummer, too! All o' you listen, she's my aunt Olivia, and she's coming home!" Suddenly the child flung out her arms towards the south where Aunt Olivia was. And though she stood quite still, something within her seemed to spring away and go hurrying through the clear air. "I shouldn't suppose Aunt Olivia would ever forgive me, but she's Aunt Olivia and she will," wrote Rebecca Mary that night, her small, dark face full of a solemn peace--it seemed so long since she had been full of peace before. She wrote on eagerly: "When she gets home Ime going to hug her I can't help it if it wont be keeping right on." Article Seven Rebecca Mary measured them. Against the woodshed wall, with chalk--it was not altogether an easy thing to do. The result startled her. With rather unsteady little fingers she measured from chalk mark to floor again, to make sure it was as bad as that. It was even a little worse. "Oh," sighed Rebecca Mary, "to think they belong to me--to think they're hitched on!" She gazed down at them with scorn and was ashamed of them. She tried to conceal their length with her brief skirts; but when she straightened up, there they were again, as long as ever. She sat down suddenly on the shed floor and drew them up underneath her. That was temporarily a relief. "If I sit here world without end nobody'll see 'em," grimly smiled Rebecca Mary. It was her legs Rebecca Mary measured against the woodshed wall. It was her legs she was ashamed of. No wonder the minister's wife had said to the minister going home from meeting, with Rebecca Mary behind them unawares,--no wonder she had said, "Robert, HAVE you noticed Rebecca Mary's legs?" Rebecca Mary had not heard the reply of the minister, for of course she had gone away then. If she had stayed she would have heard him say, with exaggerated prudery, "Felicia! My dear! Were you alluding to Rebecca Mary's limbs?" for the minister wickedly remembered inadvertent occasions when he himself had called legs legs. "LEGS," the minister's wife repeated, calmly--"Rebecca Mary's are too long for limbs. Robert, that child will grow up one of these days!" "They all do," sighed the minister. "It's human nature, dear. You'll be telling me next that there's something the matter with Rhoda's--legs." The minister's wife gazed thoughtfully ahead at a little trio fast approaching the vanishing point. Her eyes grew a little wistful. "There is now, perhaps, but I haven't noticed--I won't look!" she murmured. "And, anyway, Robert, Rhoda will give us a little time to get used to it in. But Rebecca Mary isn't the Rhoda kind--I don't believe Rebecca Mary will give us even three days of grace!" "I always supposed Rebecca Mary was born that way--grown up," the minister remarked, tucking a gloved hand comfortably close under his arm. "I wouldn't let it worry me, dear." "Oh, I don't--not worry, really," she said, smiling--"only her legs startled me a little today. If she were mine, I should let her dresses down." "If she were Rhod--" "She isn't, she's Rebecca Mary. Probably if I were Miss Olivia I would let Rhoda's down!" And she knew she would. Rebecca Mary on the woodshed floor sat and thought "deep-down" thoughts. Her eyes were fixed dreamily on a big knothole before her, and the thoughts seemed to come out of it and stand before her, demanding imperiously to be thought. One after another--a relentless procession. "Think me," the first one had commanded. "I'm the Thought of Growing Up. I saw you measuring your legs, and I concluded it was time for me to introduce myself. I had to come some time, didn't I?" "Oh yes," breathed Rebecca Mary, sadly. "I don't suppose I could expect you to stay in there always; but--but I'm not very glad to see you. You needn't have come so SUDDEN," she added, with gentle resentment. The Thought of Growing Up crept into her mind and nestled down there. As thoughts go, it was not an unkind one. "You'll get used to me sometime and like me," it said, comfortingly. But Rebecca Mary knew better. She drove it out. Why must legs keep on growing and unwelcome Thoughts come out of knotholes? Why could not little girls keep on sewing stents and learning arithmetic and carrying beautiful doll-beings to bed? Why had the Lord created little girls like this--this growing kind? "If I had made the world," began Rebecca Mary--but stopped in a hurry. The irreverence of presuming to make a better world than the Lord shamed her. "I suppose He knew best, but if He'd ever been a little girl--" This was worse than the other. Rebecca Mary hastily dismissed the world and its Maker from her musings for fear of further irreverences. One Thought came out of the knothole, illustrated. It was leading a tall woman-girl by the hand--no, it was pushing it as though the woman-girl were loath to come. "Come along," urged the new Thought, laughingly. "Here she is--this is Rebecca Mary. Rebecca Mary, this is YOU! You needn't be afraid of each other, you two. Take a good long look and get acquainted." The woman-girl was tall and straight. She had Rebecca Mary's hair, Rebecca Mary's eyes, mouth, little pointed chin. But not Rebecca Mary's legs--unless the long skirts covered them. She was rather comely and pleasant to look at. But Rebecca Mary tried not to look. "She's got a lover---some day she'll be getting married," the new Thought said more abruptly, startlingly, than grammatically. And then with a little muffled cry Rebecca Mary put out her hands and pushed the woman-girl away--back into the knothole whence she had come. The Thought, too, for she had no room in her mind for thoughts like that. "My aunt Olivia wouldn't allow me to think of you," she explained in dismissing them. "And," with dignity she added, "neither would Rebecca Mary." It was to be as the minister's wife had prophesied--there were to be not even the three days of grace allowed by law when Rebecca Mary grew up. Sitting there with her legs, her poor little unappreciated legs, the innocent cause of the whole trouble, curled out of sight, Rebecca Mary planned that there should be but one day of grace. She would allow one day more to be a little girl in, and then she would grow up. But that one day--Rebecca Mary got up hastily and went to find Aunt Olivia. "Aunt Olivia," she began, without preamble--Rebecca Mary never preambled--"Aunt Olivia, may I have a holiday tomorrow?" Aunt Olivia was rocking in her easy chair on the porch. It had taken her sixty-two years to learn to sit in an easy chair and rock. Even now, and she had been home from the hospital many months, she felt a little as though the friendly birds that perched on the porch railing were twittering tauntingly, "Plummer! Plummer! Plummer!--rocking in an easy chair!" "May I, Aunt Olivia?" It was an unusual occurrence for Rebecca Mary to ask again so soon. But this was an unusual occurrence. Aunt Olivia's thin face turned affectionately towards the child. "School doesn't begin again tomorrow, does it?" she said in surprise. Weren't all Rebecca Mary's days now holidays? "Oh no---no'm. But I mean may I skip my stents? And--and may I soak the kettles and pans? Just tomorrow." "Just tomorrow," repeated bewildered Aunt Olivia--"soak your--stents--" "Because it's going to be a pretty busy day. It's going to be a--a celebration," Rebecca Mary said, softly. There was a strangely exalted look on her face. Oddly enough she was not afraid that Aunt Olivia would say no. Aunt Olivia said yes. She did not ask any questions about the celebration, on account of the exalted look. She could wait. But the bewildered look stayed for a while on her thin face. Rebecca Mary was a queer child, a queer child--but she was a dear child. Dearness atoned for queerness in Aunt Olivia's creed. The celebration began early the next morning before Aunt Olivia was up. She lay in bed and heard it begin. Rebecca Mary out in the dewy garden was singing at the top of her voice. Aunt Olivia had never heard her sing like that before--not at the top. Her sweet, shrill voice sounded rather unacquainted with such free heights as that, and the woman in the bed wondered with a staid little smile if it did not make Rebecca Mary feel as she felt when she sat in the easy chair rocking. Rebecca Mary sang hymns mostly, but interspersed in her programme were bits of Mother Goose set to original tunes--she had learned the Mother Goose of the minister's Littlest Little Boy--and original bits set to familiar tunes. It was a wild little orgy of song. "My grief!" Aunt Olivia ejaculated under her breath; but she did not mean her grief. Other people might think Rebecca Mary was crazy--not Aunt Olivia. But yet she wondered a little and found it hard to wait. Rebecca Mary washed the breakfast cup and plates, but put the pans and kettles to soak, and hurried away to her play. There was so much playing to be done before the sun set on her opportunity. She had made a little programme on a slip of paper, with approximate times allotted to each item. As: Tree climbing... 1 hr. (Do not tare anything) Mud pies... 1 hr. and 1/2. (Do not get anything muddy) Tea party... 2 hrs. (Do not break anything) Skipping... 1/2 hr. Rebecca Mary had written 1 hr. at first opposite skipping, but it had rather appalled her to think of skipping for so long a period of time, and, with a sense of being already out of breath, she had hurriedly erased the 1 and substituted 1/2. Underneath she had written, ("Do not tip over anything"). All the items had cautionary parentheses underneath them, for Rebecca Mary did not wish the celebration to injure "anything." Not this last day, when all the days of all the years before it, that had gone to make up her little girlhood, nothing had been torn or muddied or tipped over. Rebecca Mary had never climbed trees, had never made mud pies, never had tea parties, nor skipped. It was with rather a hesitating step that she went forward to meet them all. She was even a little awed. But she went. No item on her programme was omitted. From her rocker on the porch Aunt Olivia watched proceedings with quiet patience. It was a good vantage point--she could see nearly all of the celebration. The tree Rebecca Mary climbed was on the edge of the old orchard next to Aunt Olivia, and there was a providential little rift through the shrubbery and vines that intervened. This part of the programme she could see almost too clearly, for it must be confessed that this part startled Aunt Olivia out of her calm. It--it was so unexpected. She stopped rocking and leaned forward in her chair to peer more sharply. What was the child--"She's climbing a tree!" breathed Aunt Olivia in undisguised astonishment. Even as she breathed it, there came to her faintly the snapping of twigs and flutter of leaves. Then all was quite still, but she could discern with her pair of trusty Plummer eyes two long legs gently dangling. If Aunt Olivia had known, Rebecca Mary, too, was startled. It--it was so strange an experience. She was not in the least afraid--it was a mental start rather than a physical one. When she had reached the limb set down in her programme she sat on it in a little daze of bewildered delight. She liked it! "Why, why, it's nice!" Rebecca Mary breathed. Her turn had come for undisguised astonishment. The leaves all about her nodded to her and stroked her cheeks and hair and hands. They whispered things into her ears. They were such friendly little leaves! Nothing looked quite the same up there. It was a little as if she were in a new world, and she felt odd thrills of pride, as probably people who had discovered countries and rivers and north poles felt. Through a rift in the leaves she could see with her good Plummer eyes a swaying spot of brown and white that was Aunt Olivia rocking. Suddenly Rebecca Mary experienced a pang of remorse that she had wasted so many opportunities like this--that this was her only one. She wished she had put 2 hrs. instead of 1 hr. over against "Tree climbing," but it was too late now. She had borrowed Aunt Olivia's open-faced gold watch to serve as timekeeper, and promptly at the expiration of the 1 hr. she slid down through the crackling twigs and friendly leaves to the old world below. She did not allow herself to look back, but she could not help the sigh. It was going to be harder to grow up than she had thought it would be. The mud pies she made with conscientious care as Rhoda, the minister's little girl, had said she used to make them. She made rows and rows of them and set them in the sun to bake. There were raisin stones in them all and crimped edges around them. It did not take nearly all the 1 hr. and 1/2, so she made another and still another batch. When the time was up she did not sigh, but she had had rather a good time. How many mud pies she HADN'T made in all those years that were to end today! Olivicia and the little white cat went to the tea party. Rebecca Mary thought of inviting Aunt Olivia--she got as far as the porch steps, but no farther. She caught a glimpse of her own legs and shrank back sensitively. They seemed to have grown since she measured them against the woodshed wall. Rebecca Mary felt the contrast between her legs and the tea party. Aunt Olivia never knew how near she had come to being invited to take part in the celebration, at Article III. on the programme. Rhoda had had tea parties unnumbered, like the sands of the sea. She had described them fluently, so Rebecca Mary was not as one in the dark. She knew how to cut the bread and the cake into tiny dice, and the cookies into tiny rounds. She knew how to make the cambric tea and to arrange the jelly and flowers. But Rhoda had forgotten to tell her how to make a rose pie--how to select two large rose leaves for upper and under crust, and to fill in the pie between them with pink and white rose petals and sugar in alternate layers. Press until "done." Why had Rhoda forgotten? It seemed a pity that there was no rose pie at Rebecca Mary's tea party--and no time left to make one. "Will you take sugar in your tea, Olivicia?" Rebecca Mary asked, shyly. She sat on the ground with her legs drawn under her out of sight, but there were little warm spots in her cheeks. She had not expected to be--ashamed. If there had been a knothole anywhere, she thought to herself, the Thought of Growing Up would have come out of it and confronted her and reminded her of her legs. "Will you help yourself to the bread? Won't you have another cookie?" She left nothing out, and gradually the strangeness wore away. It got gradually to be a good time. "How many tea parties," thought Rebecca Mary, "there might have been!" Rebecca Mary was skipping, when the minister's wife came to call on Aunt Olivia. It was the minister's wife who discovered it. Aunt Olivia caught the indrawing of her breath and saw her face. Then Aunt Olivia discovered it, and a delicate color overspread her thin cheeks and rose to her temples. Now what was the child-- "Rhoda is a great skipper," the minister's wife said, hurriedly. But it was the wrong thing--she knew it was the wrong thing. "Rebecca Mary is having a--celebration," hurried Aunt Olivia; but she wished she had not, for it seemed like trying to excuse Rebecca Mary. She, too, had said the wrong thing. "How pleasant it is out here!" tried again the minister's wife. "Yes, it's cool," Aunt Olivia agreed, gratefully. After that the things they said were right things. The fantastic little figure down there in the orchard, skipping wildly, determinedly, was in none of them. Both of them felt it to be safer. But the minister's wife's gaze dwelt on the skipping figure and followed it through its amazing mazes, in spite of the minister's wife. "I couldn't have helped it, Robert," she said. "Not if you'd been there preaching 'Thou shalt not' to me! You would have looked too, while you were preaching. You can't imagine, sitting there at that desk, what the temptation was--Robert, you don't suppose Rebecca Mary has gone crazy?" "Felicia! You frighten me!" "No, _I_ don't suppose either. But it was certainly very strange. It was almost ALARMING, Robert. And she didn't know how at all. I wanted to go down and show her!" "It seems to me"--the minister spoke impressively "that it is not Rebecca Mary who has gone crazy--" "Why, the idea! Haven't I made it plain?" laughed she. "I'll speak in A B C's then. Rebecca Mary was SKIPPING, Robert--skipping skipping." "Then it's Rebecca Mary," the minister murmured. "That's what I'm afraid--didn't I say so? Or else it's her second childhood--" "First, you mean. If THAT'S it, don't let's say a word, dear--don't breathe, Felicia, for fear we'll stop it." "Dear child!" the minister's wife said, tenderly. "I wish I'd gone down there and shown her how. And I'd have told her--Robert, I'd have told her how to climb a tree! Don't tell the parish." The day was to end at sunset, from sunrise to sunset, Rebecca Mary had decreed. The last article on her crumpled little programme was, "Saying Good-by to Olivicia(Don't cry)." It was going to be the most difficult thing of all the articles. Olivicia had existed so short a time comparatively--it might not have been as difficult if there had always been an Olivicia. "Or it might have been harder," Rebecca Mary said. She went towards that article with reluctant feet. But it had to come. The bureau drawer was all ready. Rebecca Mary had lined it with something white and soft and sweetened it with dried rose petals spiced in the century-old Plummer way. It bore rather grewsome resemblance to Olivicia's coffin, but it was not grewsome to Rebecca Mary. She laid the doll in it with the tender little swinging motion mothers use in laying down their tiny sleepers. "There, there the-re!" crooned Rebecca Mary, softly, brooding over the beautiful being. "You'll rest there sweetly after your mother is grown up. And you'll try not to miss her, won't you? You'll understand, Olivicia?--oh, Olivicia!" But she did not cry. Her eyes were very bright. For several minutes she stood there stooped over painfully, gazing down into the cof--the bureau drawer, wherein lay peaceful Olivicia. She was saying good-bye in her heart--she never said it aloud. "Dear," very softly indeed, "you are sure you understand? Everybody has to grow up, dear. It--it hurts, but you have to. I mean I'VE got to. I wouldn't so soon if it wasn't for my legs. But they keep right on growing--they're awful, dear!--I can't stop 'em. Olivicia, lie right there and be thankful you're a doll! But I wish you could open your eyes and look at me just once more." Rebecca Mary shut the drawer gently. It was over--no, she would say one thing more to the beautiful being in there. She bent to the keyhole. "Olivicia!" she called in a tender whisper, "I shall be right here nights. We shan't be far away from each other." But it would not be like lying in each other's arms--oh, not at all like that. Rebecca Mary caught her breath; it was perilously like a sob. Then she girded up her loins and went away to meet her fate--the common fate of all. She was very tired. The day had been a strain upon her that was beginning now to tell. To put all one's childhood into one day--that is not easy. Article VI. was the last. In a way, it was a rest to Rebecca Mary, for it entailed merely a visit to the woodshed. She could sit quietly on the floor opposite the knothole and wait for the Thoughts. If the Thought of Growing Up came out tonight, she would say: "Oh, well, you may stay--you needn't go back. I'm not any glad to see you, but I'm ready. I suppose I shall get used to you." What Thoughts came out of the knothole to Rebecca Mary she never told to any one. It was nearly dark when she went away, planting her feet firmly, holding her head straight--Rebecca Mary Plummer. She went to find Aunt Olivia and tell her. On the way, she stopped to get Aunt Olivia's shawl, for it was getting chilly out on the porch. Significantly the first thing Rebecca Mary did after she began to grow up was to get the shawl and lay it over Aunt Olivia's spare shoulders. The second thing was to bend to the scant gray hair and lightly rub it with her cheek. It was a Rebecca Mary kiss. Out in front of the rocking chair, still straight and firm, she told Aunt Olivia. "It's over--I think I put everything in," she said. "I thought you ought to know, so I came to tell you. I'm ready to grow up." After all, if Rebecca Mary had known, her "programme" had not ended with Article VI. Here was another. Take the pencil in your steady little fingers, Rebecca Mary, and write: Article VII.--Growing up. (Do not break Aunt Olivia's heart.) Un-Plummered Aunt Olivia sighed. It was the third time since she had begun to let Rebecca Mary down. The third sigh was the longest one. Oh, this letting down of children who would grow up! "I won't do it!" Aunt Olivia rebelled, fiercely, but she took up her scissors again at Duty's nudge. "You don't want people laughing at her, do you?" Duty said, sensibly. "Well, then, rip out that hem and face up that skirt and stop sighing. What can't be cured must be endur--" "I'm ripping it out," Aunt Olivia interrupted, crisply. But Duty was not to be silenced. "You ought to have done it before," dictatorially. "You've known all along that Rebecca Mary was growing up." Aunt Olivia, like the proverbial worm, turned. "I didn't know till Rebecca Mary told me," she retorted; then the rebellion died out of her thin face and tenderness came and took its place. Aunt Olivia was thinking of the time when Rebecca Mary told her. She gazed past Duty, past the skirt across her knees, out through the porch vines, and saw Rebecca Mary coming to tell her. She saw the shawl the child was bringing, felt it laid on her shoulders, and something else laid on her hair, soft and smooth like a little, lean, brown cheek. The memory was so pleasant that Aunt Olivia closed her eyes to make it stay. When she opened them some one was coming along the path, but it was not Rebecca Mary. "Good afternoon!" some one said. Aunt Olivia stiffened into a Plummer again with hurried embarrassment. She did not recognize the voice nor the pleasant young face that followed it through the vines. "It's Rebecca Mary's aunt, isn't it?" The stranger smiled. "I should know it by the family resemblance." "We're both Plummers," Aunt Olivia answered, gravely. "Won't you come up on the porch and take a seat?" "No, I'll sit down here on the steps--I'd rather. I think I'll sit on the lowest step for I've come on a very humble errand! I'm Rebecca Mary's teacher." "Oh!" It was all Aunt Olivia could manage, for a sudden horror had come upon her. She had a distinct remembrance of being at the Tony Trumbullses when the school teacher came to call. "It's--it's rather hard to say it." The young person on the lowest step laughed nervously. "I'd a good deal rather not. But I think so much of Rebecca Mary--" The horror grew in Aunt Olivia's soul. It was something terribly like that the Tony Trumbullses' teacher had said. And like this: "It hurts--there! But I made up my mind it was my duty to come up here and say it, and so I've come. I'm sorry to have to say--" "Don't!" ejaculated Aunt Olivia, trembling on her Plummer pedestal. For she was laboring with the impulse to refuse to listen to this intruder, to drive her away--to say: "I won't believe a word you say! You may as well go home." "Hoity-toity!" breathed Duty in her ear. It saved her. "Well?" she said, gently. "Go on." "I'm sorry to say I can't teach Rebecca Mary any more, Miss Plummer. That's what I came to tell you--" This was awful--awful! But hot rebellion rose in Aunt Olivia's heart. There was some mistake--it was some other Rebecca Mary this person meant. She would never believe it was HERS--the Plummer one! "Because I've taught her all I know. There! Do you wonder I chose the lowest step to sit on? But it's the truth, honest," the little teacher laughed girlishly, but there were shame spots on her cheeks--"Rebecca Mary is the smartest scholar I've got, and I've taught her all I know." In her voice there was confession to having taught Rebecca Mary a little more than that. The shame spots flickered in a halo of humble honesty. "She's been from Percentage through the arithmetic four times--Rebecca Mary's splendid in arithmetic. And she knows the geography and grammar by heart." The look on Aunt Olivia's face! The transition from horror to pride was overwhelming, transfiguring. "Rebecca Mary's smart," added the honest one on the doorstep. "_I_ think she ought to have a chance. There! That's all I came for, so I'll be going. Only, I don't suppose--you don't think you'll have to tell Rebecca Mary, do you? About--about me, I mean?" "No, I don't," Aunt Olivia assured her, warmly. Her thin, lined hand met and held for a moment the small, plump one--long enough to say, "You're a good girl--I like you," in its own way. The little teacher went away in some sort comforted for having taught Rebecca Mary all she knew. She even hummed a relieved little tune on her way home, because of the pleasant tingle in the hand that Rebecca Mary's aunt had squeezed. After all, no matter how much you dreaded doing it, it was better to tell the truth. Aunt Olivia hummed no relieved little tune. The pride in her heart battled with the Dread there and went down. Aunt Olivia did not call the Dread by any other name. It was Duty who dared. Confronting Aunt Olivia: "I suppose you know what it means? I suppose you know it means you've got to give Rebecca Mary a chance? When are you going to send her away to school?" "Oh--don't!" pleaded Aunt Olivia. "You don't give me any time. There's no need of hurry--" "I'm still a Plummer, if you're not," broke in Duty, with ironic sharpness. "The Plummers were never afraid to look their duty in the face." "I'm--I'm looking at you," groaned Aunt Olivia, climbing painfully back on to her pedestal. "Go ahead and say it. I'm ready--only I guess you've forgot how long I've had Rebecca Mary. When you've brought a child up--" "I brought her up myself," calmly. "I ought to know. She wouldn't have been Rebecca Mary, would she, if I hadn't been right on hand? Who was it taught her to sew patchwork before she was four years old? And make sheets--and beds--and bread? Who was it kept her from being a little tomboy like the minister's girl? Who taught her to walk instead of run, and eat with her fork, and be a lady? Who was it--" "Oh, you--you!" sighed Aunt Olivia, trembling for her balance. "You did 'em all. I never could've alone." "Then"--Duty was justly complacent--"Then perhaps you'll be willing to leave Rebecca Mary's going away to school to me. She must go at once, as soon as you can get her read--" Aunt Olivia tumbled off. She did not wait to pick herself up before she turned upon this Duty that delighted in torturing her. "You better get her ready yourself! You better let her down and make her some nightgowns and count her pocket-handkerchiefs! You think you can do anything--no, I'M talking now! I guess it's my turn. I guess I've waited long enough. Maybe you brought Rebecca Mary up, but I'm not going to leave it to you whether she'd ought to go away to school. She's my Rebecca Mary, isn't she? Well? It's me that loves her, isn't it--not you? If I can't love her and stay a Plummer, then I'll--love her. I'm going to leave it to the minister." The minister was a little embarrassed. The wistful look in Aunt Olivia's eyes said, "Say no" so plainly. And he knew he must say yes--the minister's Duty was imperative, too. "If she can't get any more good out of the school here--" he began. "She can't," said Aunt Olivia's Duty for her. "The teacher says she can't. Rebecca Mary's smart." Then Duty, too, was proud of Rebecca Mary! "I know she is," said the minister, heartily. "My Rhoda--you ought to hear my Rhoda set her up. She thinks Rebecca Mary knows more than the teacher does." "Rhoda's smart, too," breathed Duty in Aunt Olivia's ear. "So you see, dear Miss Olivia, the child would make good use of any advantage--" "You mean I ought to send her away? Well, I'm ready to--I said I'd leave it to you. Where shall I send her? If there was only--I don't suppose there's some place near to? Children go home Friday nights sometimes, don't they?" "There is no school near enough for that, I'm afraid," the minister said, gently. He could not bear the look in Miss Olivia's eyes. "It hurt," he told his wife afterwards. "I wish she hadn't asked me, Felicia." "I know, dear, but it's the penalty of being a minister. Ministers' hearts ought to be coated with--with asbestos or something, so the looks in people's eyes wouldn't burn through. I'm glad she didn't ask ME!" "It will nearly kill them both," ran on the minister's thoughts, aloud. "You know how it was when Miss Olivia was at the hospital." "Robert!"--the minister's wife's tone was reproachful--"you're talking in the future tense! You said 'will.' Then you advised her to send Rebecca Mary away!" "Guilty," pleaded the minister. "What else could I do?" "You could have offered to teach her yourself"--with prompt inspiration. "Oh, Robert, why didn't you?" "Felicia!--my dear!"--for the minister was modest. "You know plenty for two Rebecca Marys," she triumphed. "Didn't you appropriate all the honors at college, you selfish boy!" "It's too late now, dear." But the minister's eyes thanked her, and the big clasp of his arms. A minister may be mortal. "Maybe it is and maybe it isn't," spoke the minister's wife, in riddles. "We'll wait and see." "But, Felicia--but, dear, they're both them Plummers." "Maybe they are and maybe they aren't," laughed she. That night Aunt Olivia told Rebecca Mary--after she went to bed, quite calmly: "Rebecca Mary, how would you like to go away to school? For I'm going to send you, my dear." "'Away--to school--my dear!'" echoed Rebecca Mary, sitting upright in bed. Her slight figure stretched up rigid and preternaturally tall in the dim light. "Yes; the minister advises it--I left it to him. He thinks you ought to have advantages." Aunt Olivia slipped down suddenly beside the little rigid figure and touched it rather timidly. She felt a little in awe of the Rebecca Mary who knew more than her teacher did. "They all seem to think you're--smart, my dear," Aunt Olivia said, and she would scarcely have believed it could be so hard to say it. For the life of her she could not keep the pride from pricking through her tone. The wild temptation to sell her Plummer birthright for a kiss assailed her. But she groped in the dimness for Duty's cool touch and found it. In the Plummer code of laws it was writ, "Thou shalt not kiss." "I'm going right to work to make you some new nightgowns," Aunt Olivia added, hastily. "I think I shall make them plain," for it was in the nature of a reinforcement to her courage to leave off the ruffles. Rebecca Mary's eyes shone like stars in the dark little room. The child thought she was glad to be going away to school. "Shall I study algebra and Latin?" she demanded. "I suppose so--that'll be what you go for." "And French--not FRENCH?" "Likely." Rebecca Mary fell back on the pillows to grasp it. But she was presently up again. "And that thing that tells about the air and--and gassy things? And the one that tells about your bones?" Aunt Olivia did not recognize chemistry, but she knew bones. She sighed gently. "Oh yes; I suppose you'll find out just how you're put together, and likely it'll scare you so you won't ever dare to breathe deep again. Maybe learning like that is important--I suppose the minister knows." "The minister knows everything," Rebecca Mary said, solemnly. "If you let me go away to school, I'll try to learn to know as much as he does, Aunt Olivia. You don't--you don't think he'd mind, do you?" In the dark Aunt Olivia smiled. The small person there on the pillows was, after all, a child. Rebecca Mary had not grown up, after all! "He won't mind," promised Aunt Olivia for the minister. She went away presently and cut out Rebecca Mary's new nightgowns. She sat and stitched them, far into the night, and stitched her sad little bodings in, one by one. Already desolation gripped Aunt Olivia's heart. Rebecca Mary's dreams that night were marvelous ones. She dreamed she saw herself in a glass after she had learned all the things there were to learn, and she looked like the minister! When she spoke, her voice sounded deep and sweet like the minister's voice. Somewhere a voice like the minister's wife's seemed to be calling "Robert! Robert!" "Yes?" answered Rebecca Mary, and woke up. There were many preparations to make. The days sped by busily, and to Rebecca Mary full of joyous expectancy. Aunt Olivia made no moan. She worked steadily over the plain little outfit and thrust her Dreads away with resolute courage, to wait until Rebecca Mary was gone. Time enough then. "You're doing right--that ought to comfort you," encouraged Duty, kindly. "Clear out!" was what Aunt Olivia cried out, sharply, in answer. "You've done enough--this is all your work! Don't stand there hugging yourself. YOU'RE not going to miss Rebecca Mary--" "I shall miss her," Duty murmured. "I was awake all night, too, dreading it. You didn't know, but I was there." The last day, when it came, seemed a little--a good deal--like that other day when Aunt Olivia went away, only it was the other way about this time. Rebecca Mary was going away on this day. The things packed snugly in the big valise were her things; it was she, Rebecca Mary, who would unpack them in a wondrous, strange place. It was Rebecca Mary the minister's wife and Rhoda came to bid good-bye. Aunt Olivia went to the station in the stage with the child. She did not speak much on the way, but sat firmly straight and smiled. Duty had told her the last thing to smile. But Duty had not trusted her; unseen and uninvited, Duty had slipped into the jolting old vehicle between Aunt Olivia and Rebecca Mary. "She isn't the Plummer she was once," sighed Duty. But at the little station, in those few final moments, two Plummers, an old one and a young one, waited quietly together. Neither of them broke down nor made ado. Duty retired in palpable chagrin. "Good-bye, my dear," Aunt Olivia said, steadily, though her lips were white. "Good-bye, Aunt Olivia," Rebecca Mary Plummer said, steadily. "I'm very MUCH obliged to you for sending me." "You're--welcome. Don't forget to wear your rubbers. I put in some liniment in case you need it--don't get any in your eyes." Outside on the platform Aunt Olivia sought and found Rebecca Mary's window and stood beside it till the train started. Through the dusty pane their faces looked oddly unfamiliar to each other, and the two pairs of eyes that gazed out and in had a startled wistfulness in them that no Plummer eyes should have. If Duty had staid-- The train shook itself, gave a jerk or two, and plunged down the shining rails. Aunt Olivia watched it out of sight, then turned patiently to meet her loneliness. The Dreads came flocking back to her as if she had beckoned to them. For now was the time. The letters Rebecca Mary wrote were formally correct and brief. There was no homesickness in them. It was pleasant at the school, that book about bones was going to be very interesting. Aunt Olivia was not to worry about the rubbers, and Rebecca Mary would never forget to air her clothes when they came from the wash. Yes, she had aired the nightgown that Aunt Olivia ironed the last thing. No, she hadn't needed any liniment yet, but she wouldn't get any in her eyes. Aunt Olivia's letters were to the point and calm, as though Duty stood peering over her shoulder as she wrote. She was glad Rebecca Mary liked the bones, but she was a little surprised. She was glad about the rubbers and the wash; she was glad there had been no need yet for the liniment. It was a good thing to rub on a sore throat. The minister's wife had been over with her work she said Rhoda missed Rebecca Mary. Yes, the little, white cat was well--no, she hadn't caught any mice. The calla lily had two buds, the Northern Spy tree was not going to bear very well. "Robert, I've been to see Miss Olivia," the minister's wife said at tea. "Yes?" The minister waited. He knew it was coming. "She was knitting stockings for Rebecca Mary. Robert, she sat there and smiled till I had to come home to cry!" "My dear!--do you want me to cry, too?" "I'm a-going to," sniffed Rhoda. "I feel it coming." "She is so lonely, Robert! It would break your heart to see her smile. How do I know she is? Oh no--no, she didn't say she was! But I saw her eyes and she let the little, white cat get up in her lap!" "Proof enough," the minister said, gently. Between the two of them--the child at school and Aunt Olivia at home--letters came and went for six weeks. Aunt Olivia wrote six, Rebecca Mary six. All the letters were terse and brief and unemotional. Weather, bones, little white cats, liniment--everything in them but loneliness or love. Rebecca Mary began all hers "Dear Aunt Olivia," and ended them all "Respectfully your niece, Rebecca Mary Plummer." "Dear Rebecca Mary," began Aunt Olivia's. "Your aff. aunt, Olivia Plummer," they closed. Yet both their hearts were breaking. Some hearts break quicker than others; Plummer hearts hold out splendidly, but in the end-- In the end Aunt Olivia went to see the minister and was closeted with him for a little. The minister's wife could hear them talking--mostly the minister--but she could not hear what they said. "It's come," she nodded, sagely. "I was sure it would. That's what the little, white cat purred when she rubbed against my skirts, 'She can't stand it much longer. She doesn't sleep nights nor eat days--she's giving out.' Poor Miss Olivia!--but I can't understand Rebecca Mary." "It's the Plummer in her," the little, white cat would have purred. "You wait!" Aunt Olivia turned back at the minister's study door. "Then you will?" she said, eagerly. "You're perfectly willing to? I don't want to feel--" "You needn't feel," the minister smiled. "I'm more than willing. I'm delighted. But in the matter of--er--remuneration, I cannot let you--" "You needn't let me," smiled Miss Olivia; "I'll do it without." She was gently radiant. Her pitifully thin face, so transfigured, touched the big heart of the minister. He went to his window and watched the slight figure hurry away. He would scarcely have been surprised to see it turn down the road that led towards the railway station. "Oh, Robert!" It was the minister's wife at his elbow. "You dear boy, I know you've promised! You needn't tell me a thing--didn't I suggest it in the first place? Dear Miss Olivia--I'm so glad, Robert! So are you glad, you minister!" But they were neither of them thinking of little, stubbed-out shoes that would be easier to buy. Aunt Olivia turned down the station road the next morning, in the swaying old stage. Her eager gaze never left the plodding horses, as if by looking at them she could make them go faster. "They're pretty slow, aren't they?" she said. "Slow--THEM? Well, I guess you weren't never a stage horse!" chuckled the old man at the reins. "No," admitted Aunt Olivia, "I never was, but I know I'd go faster today." At the Junction, halfway to Rebecca Mary, she descended alertly from the train and crossed the platform. She must wait here, they told her, an hour and twenty minutes. On the other side of the station a train was just slowing up, and she stood a moment to scan idly the thin stream of people that trickled from the cars. There were old women--did any of them, she wondered, feel as happy as she did? There were tall children, too. There was one--Aunt Olivia started a little and fumbled in her soft hair, under the roses in her bonnet brim, for her glasses. There was one tall child--she was coming this way--she was coming fast--she was running! Her arms were out-- "Aunt Olivia! Aunt Olivia!" the Tall Child was crying out, joyously, "Oh, Aunt Olivia!" "Rebecca Mary!--my dear, my dear!" They were in each other's arms. The roses on Aunt Olivia's bonnet brim slipped to one side--the two of them, not Plummers any more, but a common, glad old woman and a common, glad, tall child, were kissing each other as though they would never stop. The stream of people reached them and flowed by on either side. Trains came and went, and still they stood like that. "Hoity-toity!" muttered Aunt Olivia's Duty, and slipped past with the stream. A Plummer to the end, what use to stay any longer there? "I was coming home," cried Rebecca Mary. "I couldn't bear it another minute!" "I was coming after you--my dear, my DEAR, _I_ couldn't bear it another minute!" End of the Project Gutenberg EBook of Rebecca Mary, by Annie Hamilton Donnell ***	{ "pile_set_name": "Gutenberg (PG-19)" }
/**************************************************************************\ \| \| \| Copyright 2001-2004 NVIDIA Corporation. All Rights Reserved. \| \| \| \| THE INFORMATION CONTAINED HEREIN IS PROPRIETARY AND CONFIDENTIAL \| \| TO NVIDIA, CORPORATION. USE, REPRODUCTION OR DISCLOSURE TO ANY \| \| THIRD PARTY IS SUBJECT TO WRITTEN PRE-APPROVAL BY NVIDIA, CORP. \| \| \| \| THE INFORMATION CONTAINED HEREIN IS PROVIDED "AS IS" WITHOUT \| \| EXPRESS OR IMPLIED WARRANTY OF ANY KIND, INCLUDING ALL IMPLIED \| \| WARRANTIES OF MERCHANTABILITY, NONINFRINGEMENT, AND FITNESS FOR A \| \| PARTICULAR PURPOSE. \| \| \| \*************************************************************************/ / FILE: os.h DATE: 2/7/00 This file contains the os interface. Note that the os interface is itself an OS-independent API. The OS specific module is implemented by ndis.c for Win9X/NT and linuxnet.c for linux. / #ifndef _OS_H_ #define _OS_H_ #include "phy.h" #define HDO_VERSION_STRING "HDR O: $Revision: #21 $"; // This is the maximum packet size that we will be sending // #define MAX_PACKET_SIZE 2048 //#define RX_BUFFER_SIZE 2048 #define MIN_PACKET_MTU_SIZE 576 #define MAX_PACKET_MTU_SIZE 9202 #define MAX_PACKET_SIZE_2048 2048 #define MAX_PACKET_SIZE_1514 1514 #define MAX_PACKET_SIZE_1518 1518 #define MAX_PACKET_SIZE_JUMBO (9 1024) typedef struct _MEMORY_BLOCK { PNV_VOID pLogical; PNV_VOID pPhysical; NV_UINT32 uiLength; } MEMORY_BLOCK, PMEMORY_BLOCK; #define ALLOC_MEMORY_NONCACHED 0x0001 #define ALLOC_MEMORY_ALIGNED 0x0002 typedef struct _MEMORY_BLOCKEX { PNV_VOID pLogical; PNV_VOID pPhysical; NV_UINT32 uiLength; / Parameter to OS layer to indicate what type of memory is needed / NV_UINT16 AllocFlags; NV_UINT16 AlignmentSize; //always power of 2 / Following three fields used for aligned memory allocation / PNV_VOID pLogicalOrig; NV_UINT32 pPhysicalOrigLow; NV_UINT32 pPhysicalOrigHigh; NV_UINT32 uiLengthOrig; } MEMORY_BLOCKEX, PMEMORY_BLOCKEX; // The typedefs for the OS functions typedef NV_API_CALL NV_SINT32 (* PFN_MEMORY_ALLOC) (PNV_VOID pOSCX, PMEMORY_BLOCK pMem); typedef NV_API_CALL NV_SINT32 (* PFN_MEMORY_FREE) (PNV_VOID pOSCX, PMEMORY_BLOCK pMem); typedef NV_API_CALL NV_SINT32 (* PFN_MEMORY_ALLOCEX) (PNV_VOID pOSCX, PMEMORY_BLOCKEX pMem); typedef NV_API_CALL NV_SINT32 (* PFN_MEMORY_FREEEX) (PNV_VOID pOSCX, PMEMORY_BLOCKEX pMem); typedef NV_API_CALL NV_SINT32 (* PFN_CLEAR_MEMORY) (PNV_VOID pOSCX, PNV_VOID pMem, NV_SINT32 iLength); typedef NV_API_CALL NV_SINT32 (* PFN_STALL_EXECUTION) (PNV_VOID pOSCX, NV_UINT32 ulTimeInMicroseconds); typedef NV_API_CALL NV_SINT32 (* PFN_ALLOC_RECEIVE_BUFFER) (PNV_VOID pOSCX, PMEMORY_BLOCK pMem, PNV_VOID ppvID); typedef NV_API_CALL NV_SINT32 ( PFN_FREE_RECEIVE_BUFFER) (PNV_VOID pOSCX, PMEMORY_BLOCK pMem, PNV_VOID pvID); typedef NV_API_CALL NV_SINT32 (* PFN_PACKET_WAS_SENT) (PNV_VOID pOSCX, PNV_VOID pvID, NV_UINT32 ulSuccess); typedef NV_API_CALL NV_SINT32 (* PFN_PACKET_WAS_RECEIVED) (PNV_VOID pOSCX, PNV_VOID pvADReadData, NV_UINT32 ulSuccess, NV_UINT8 pNewBuffer, NV_UINT8 uc8021pPriority); typedef NV_API_CALL NV_SINT32 ( PFN_LINK_STATE_HAS_CHANGED) (PNV_VOID pOSCX, NV_SINT32 nEnabled); typedef NV_API_CALL NV_SINT32 (* PFN_ALLOC_TIMER) (PNV_VOID pvContext, PNV_VOID ppvTimer); typedef NV_API_CALL NV_SINT32 ( PFN_FREE_TIMER) (PNV_VOID pvContext, PNV_VOID pvTimer); typedef NV_API_CALL NV_SINT32 (* PFN_INITIALIZE_TIMER) (PNV_VOID pvContext, PNV_VOID pvTimer, PTIMER_FUNC pvFunc, PNV_VOID pvFuncParameter); typedef NV_API_CALL NV_SINT32 (* PFN_SET_TIMER) (PNV_VOID pvContext, PNV_VOID pvTimer, NV_UINT32 dwMillisecondsDelay); typedef NV_API_CALL NV_SINT32 (* PFN_CANCEL_TIMER) (PNV_VOID pvContext, PNV_VOID pvTimer); typedef NV_API_CALL NV_SINT32 (* PFN_PREPROCESS_PACKET) (PNV_VOID pvContext, PNV_VOID pvADReadData, PNV_VOID ppvID, NV_UINT8 pNewBuffer, NV_UINT8 uc8021pPriority); typedef NV_API_CALL PNV_VOID (* PFN_PREPROCESS_PACKET_NOPQ) (PNV_VOID pvContext, PNV_VOID pvADReadData); typedef NV_API_CALL NV_SINT32 (* PFN_INDICATE_PACKETS) (PNV_VOID pvContext, PNV_VOID ppvID, NV_UINT32 ulNumPacket); typedef NV_API_CALL NV_SINT32 ( PFN_LOCK_ALLOC) (PNV_VOID pOSCX, NV_SINT32 iLockType, PNV_VOID ppvLock); typedef NV_API_CALL NV_SINT32 ( PFN_LOCK_ACQUIRE) (PNV_VOID pOSCX, NV_SINT32 iLockType, PNV_VOID pvLock); typedef NV_API_CALL NV_SINT32 (* PFN_LOCK_RELEASE) (PNV_VOID pOSCX, NV_SINT32 iLockType, PNV_VOID pvLock); typedef NV_API_CALL PNV_VOID (* PFN_RETURN_BUFFER_VIRTUAL) (PNV_VOID pvContext, PNV_VOID pvADReadData); // Here are the OS functions that those objects below the OS interface // can call up to. typedef struct _OS_API { // OS Context -- this is a parameter to every OS API call PNV_VOID pOSCX; // Basic OS functions PFN_MEMORY_ALLOC pfnAllocMemory; PFN_MEMORY_FREE pfnFreeMemory; PFN_MEMORY_ALLOCEX pfnAllocMemoryEx; PFN_MEMORY_FREEEX pfnFreeMemoryEx; PFN_CLEAR_MEMORY pfnClearMemory; PFN_STALL_EXECUTION pfnStallExecution; PFN_ALLOC_RECEIVE_BUFFER pfnAllocReceiveBuffer; PFN_FREE_RECEIVE_BUFFER pfnFreeReceiveBuffer; PFN_PACKET_WAS_SENT pfnPacketWasSent; PFN_PACKET_WAS_RECEIVED pfnPacketWasReceived; PFN_LINK_STATE_HAS_CHANGED pfnLinkStateHasChanged; PFN_ALLOC_TIMER pfnAllocTimer; PFN_FREE_TIMER pfnFreeTimer; PFN_INITIALIZE_TIMER pfnInitializeTimer; PFN_SET_TIMER pfnSetTimer; PFN_CANCEL_TIMER pfnCancelTimer; PFN_PREPROCESS_PACKET pfnPreprocessPacket; PFN_PREPROCESS_PACKET_NOPQ pfnPreprocessPacketNopq; PFN_INDICATE_PACKETS pfnIndicatePackets; PFN_LOCK_ALLOC pfnLockAlloc; PFN_LOCK_ACQUIRE pfnLockAcquire; PFN_LOCK_RELEASE pfnLockRelease; PFN_RETURN_BUFFER_VIRTUAL pfnReturnBufferVirtual; } OS_API, *POS_API; #endif // _OS_H_	{ "pile_set_name": "Github" }
Q: DataTable group by and iterate through C# I have a datatable which was returned from database. the content is similar below: UserId \| Address \| Phone 1 blah 0123 1 blah2 3445 2 sdsdf 2343 2 ssf 2223 3 sadss 2321 This is the content of DataTable which is returned from database. Now I just would like to group the results by User Id and loop through to out put result foreach (DataRow userRow in DataTableGroupedByUser){ foreach (DataRow restOfColumns in AddressAndPhoneRows){ Output user details } } The output I would get should be: User Id: 1 Address Phone 1- blah 0123 2- blah2 3445 User Id 2: Address Phone 1- sdsdf 2343 2- ssf 2223 user Id :3 ... I hope you get the idea. Basically I do not want to query the database many times for each user but just use one query to pull all data and handle the grouping in the memory. There are also other reason for this. Is there any way to achieve this by using DataTable and filtering? A: You can use LINQ: var groupedByUserId = table.AsEnumerable().GroupBy(row => row.Field<int>("UserId")); foreach(var group in groupedByUserId) { Console.WriteLine("User Id: {0}", group.Key); Console.WriteLine("Address Phone"); int rowNum = 0; foreach(DataRow row in group) { Console.WriteLine("{0}- {1} {2}", ++rowNum, row.Field<string>("Address"), row.Field<string>("Address")); } }	{ "pile_set_name": "StackExchange" }
Burton Commercial Historic District The Burton Commercial Historic District is located in Burton, Texas. The district encompasses all or parts of seven city blocks. It contains 47 buildings, 28 of them classified as contributing. The buildings include retail stores, industrial buildings, a railroad depot and a portion of the railway right-of-way. The district was added to the National Register of Historic Places in June 11, 1991. Buildings Notable buildings in the district include: H. Knittel Store Annex-one-story frame building constructed in 1880 Meat Market-one-story brick building constructed around 1900 for F.W.E. Fischer, a prominent and early Burton merchant. Chamber of Commerce-Modern miniature frame building built around 1950 by Will Weeren. Farmer's Cotton Warehouse-one-story frame warehouse Homeyer Lumber Company-one-story frame building constructed around 1900. Lumber company was founded in 1881 by Charles W. Homeyer, a Burton resident. Old Burton State Bank-This one-story building served as Burton's first and only state bank from 1906 to 1965. Today it houses municipal offices. The Barber Shop-one-story building was built in 1906 for Fritz Buch as a grocery store. The barber shop operated from 1906 to 1986. Burton Auto Company-one-story building constructed in 1916 as the City Garage. In 1919 it changed its name to "Burton Auto Company". Gallery See also National Register of Historic Places listings in Washington County, Texas Recorded Texas Historic Landmarks in Washington County References External links Category:National Register of Historic Places in Washington County, Texas Category:Geography of Washington County, Texas Category:Historic districts on the National Register of Historic Places in Texas Category:Commercial buildings on the National Register of Historic Places in Texas	{ "pile_set_name": "Wikipedia (en)" }
U.S. Federal Government to Double its Hybrid Fleet; DOE Takes the Lead President Obama announced on March 31 that the federal government will update the federal fleet with fuel efficient hybrids and plug-in hybrid electric vehicles. To do so, the U.S. General Services Administration (GSA) will replace 5,603 of its least-fuel-efficient cars and trucks with fuel-efficient hybrids, doubling the number of hybrids in the federal fleet without increasing the total number of vehicles. GSA has also committed to purchasing approximately 100 plug-in hybrid vehicles in 2011, which will result in improved fuel efficiency as well as reductions in carbon dioxide emissions and other forms of air pollution. DOE will lead this initiative by replacing 753 vehicles with hybrids this year. This will bring the total number of DOE hybrid vehicles to 888, even as the agency trims the overall size of its vehicle fleet. These steps are part of a broad effort to implement the Executive Order signed by the President in October 2009, which calls for federal agencies to cut the government's fleet petroleum use by 30% by 2020. See the DOE press release and the article on the Executive Order from the October 7, 2009, edition of the EERE Network News.	{ "pile_set_name": "Pile-CC" }
You are here ALEC: Facilitating Corporate Influence Behind Closed Doors Through the American Legislative Exchange Council (ALEC), corporations pay to bring state legislators to one place, sit them down for a sales pitch on policies that benefit the corporate bottom line, then push "model bills" for legislators to make law in their states. Corporations also vote behind closed doors alongside politicians on this wish-list legislation through ALEC task forces. Notably absent were the real people who would actually be affected by many of those bills and policies. With legislators concentrated in one city, lobbyists descend on the conference to wine-and-dine elected officials after-hours, a process simplified by legislators' schedules being freed from home and family responsibilities. Multiple Wisconsin lobbyists for Koch Industries, the American Bail Coalition, Competitive Wisconsin, State Farm, Pfizer, and Wal Mart were in New Orleans, as were lobbyists for Milwaukee Charter School Advocates, Alliant Energy, and Johnson & Johnson. Corporations also sponsor invitation-only events like the Reynolds American tobacco company's cigar reception, attended by several Wisconsin legislators including Health & Human Services chair Leah Vukmir. ALEC's power lies not only in generating corporate-sponsored "model bills" for state legislators to make law, but that it facilitates multiple levels of influence-peddling. ALEC itself has a $7 million budget and 32 staffers. In addition to this budget, ALEC technically acts as an intermediary for about a million dollars in travel "scholarships" that pay for many legislators' trips to ALEC meetings, with corporate funds for the scholarships held in trust by ALEC. With corporate "sponsorship" of ALEC meetings, a couple million dollars flow through ALEC to put on days of workshops, meetings, and festivities. (This does not account for the dollars corporations spend for lobbyists to prepare for and meet with ALEC legislators in pursuit of their legislative agenda, nor does it take into account any campaign contributions that might result from the relationships cultivated at ALEC meetings.) Which is why ALEC National Chair and Louisiana Representative Noble Ellington told attendees at the beginning of the conference "when you see a sponsor, thank them" for their generosity and that "without them, we could not come close to doing the things we are about to do." Corporate-Sponsored Legislation The legislative sausage is ground at the task force meetings, where a body of legislators and corporate lobbyists actually vote on proposed model legislation. The meetings were closed to the press and the public. While legislators can bring proposed bills to the meeting, "the majority of proposed model bills I saw came from corporations," says Jeff Wright, a Florida teacher's union member who paid to attend the conference to observe ALEC in action. As Task Force members discussed and voted on proposed legislation, in the sessions Wright observed "the corporations and think tanks absolutely controlled the debate," he said. This does not mean corporate members always agree – Wright said a Tax and Fiscal Policy Task Force meeting included a dispute between online sellers like Amazon and brick-and-mortar retailers like Best Buy about taxing online sales. "In order for model legislation to move forward," says Wisconsin Rep. Mark Pocan, a Democrat who attended the ALEC meeting and wrote about it for the Progressive Magazine, "each task force must garner a majority of votes from each HALF. For example, if the legislator half likes an idea, but the corporate half doesn't, the bill does NOT move forward," which actually happened in a task force Rep. Pocan attended. ALEC spokeswoman Raegan Weber notes that a piece of model legislation passed by the task force still must be approved by the 22-person Board of Directors, all of whom are legislators (and all of whom are Republicans.) Nothing that the legislative board votes on, however, gets to the board unless the corporate wing of each task force has voted in favor of it. The ALECexposed.org site launched by the Center for Media and Democracy in July demonstrates that over 800 bills and resolutions voted for by corporations have been ratified by the ALEC legislators selected for its board. ALEC's National Chair, Louisiana Rep. Noble Ellington, told NPR's Terry Gross that even if the public (and the press) are not allowed inside the task force and board meetings, "We represent the public, and we are the ones who decide. So the tax-paying public is represented there at the table, because I'm there." ALEC Members Making Laws for Unrepresented Demographics At the 2011 ALEC meeting, Rep. Ellington was there, as were others who fit his demographic profile. Very, very few African-Americans or Latinos were present. "Wisdom can come from years, and it is not impossible to imagine aged white males being able to represent the interests of a diverse constituency," said Rev. Dr. Willie Gable, pastor of the Progressive Baptist Church and President of the Inter-Denominational Ministry Alliance of New Orleans, where the ALEC conference was held (a city that is 67% African-American). "But too often legislators work in a vacuum, and have little experience with other populations in their state," he said. Even if corporations are partnering with legislators who agree with (or can be influenced by) their interests or ideology, Rev. Gable continued, "if they are not bringing in, listening to, or considering the voices of a diverse public, they are not preparing legislation for the masses, but for themselves and corporations." The polling place restriction labeled as "voter ID" is one example of an ALEC initiative that predominantly affects those who were not represented at ALEC meetings. Like many other states in 2011, Wisconsin passed a bill earlier this year that echoes the ALEC legislation and will disproportionately impact people of color: more than half of Wisconsin's African-American and Latino residents do not have a driver's license or photo ID, but do have proof of residency that has traditionally been accepted at polling places. College students and the elderly will also be affected. Offering a free ID does little to remedy these issues – the problem is not the cost of ID but the obstacles to obtaining it. States like South Carolina are finding that tens of thousands of largely African-American elderly residents don't have the birth certificate necessary to receive an ID because they were born in their rural homes. In cities like Milwaukee with few Department of Motor Vehicles offices, acquiring an ID just so a person can vote requires taking a day off work and a long bus ride, a burden that leaders like Jesse Jackson have called akin to a "poll tax." ALEC's Weber notes that even if a "model bill" is created without the input of certain stakeholders, it still must pass through the legislative process, at which point the non-corporate voices absent from the ALEC conference can be heard. But the Wisconsin experience suggests otherwise, with resident Nicole Schulte observing that "the fact that there is a superficial chance for public input [once a bill is introduced] makes no difference" when partisan politicians are determined to force through legislation despite public opposition. Schulte participated in hearings against Wisconsin's ALEC-influenced Voter ID law, saying that "despite the legislature hearing from the public," efforts to ameliorate the effect of the bill were thwarted in party-line votes against compromises and amendments. Indeed, Louisiana Governor Bobby Jindal, an ALEC alum and the 2011 recipient of ALEC's highest honor, the "Thomas Jefferson Freedom Award," repeatedly praised the power of obstinance, proclaiming to ALEC members that when legislating, "it pays to be stubborn."	{ "pile_set_name": "Pile-CC" }
Sara, Yo, what's up? How are things across the street? Let me guess, you got all rested up saturday and sunday, then when out three nights already this week, and now are ready to go home, do laundry and sleep. Unfortunately, I've been extremely lame, mostly because you got me sick...well maybe not. Anyway, I haven't been feeling so hot, yet I did oversleep by two hours this morning which really helped. Poor Ted had to pick the slack. So, any big plans for the weekend besides laundry? Superbowl? Happy hour? Toilet flushing into the phone? Stupid drunk? Mat	{ "pile_set_name": "Enron Emails" }
Daily Knicks (El-Nazr McDowell) —The Knicks’ front office scouted additional players they think are building blocks to the organization’s goals. Only this time, the Knicks invite an unexpected local from New York. According to Ari Kramer of Newsday, the New York Knicks recently scouted East Northport native Luke Petrasek of the Columbia Lions. An unanticipated prospect, his 6’10” size and... Daily Knicks (Maxwell Ogden) —The rumor that the New York Knicks could pursue a second first-round draft pick is gaining traction. New York will host 2017 NBA Draft prospect Justin Jackson for a workout. Ian Begley of ESPN New York recently reported that the New York Knicks are interested in acquiring a second first-round selection in the 2017 NBA Draft. The possibility […] Knicks Rumors: NYK To Host 2017 NBA Draft... Daily Knicks (Maxwell Ogden) —New York Knicks stars Derrick Rose and Carmelo Anthony cracked the ESPN World Fame 100. Find out how high they ranked on the list. If no other selling point exists, playing for the New York Knicks means an immediate rise in recognizability and fame. The New York market is as powerful as any in the world, […] New York Knicks: Derrick Rose, Carmelo Anthony Crack World Fame 100 - Daily... Daily Knicks (Maxwell Ogden) —The New York Knicks struck gold in the second round of the 2015 NBA Draft with Willy Hernangomez. Who might be this year’s diamond in the rough? Perhaps the best word to describe the 2017 NBA Draft is, “Deep.” Star potential exists at the top, and when the New York Knicks look further down the board, there […] New York Knicks: Deep Sleepers To Consider In 2017 NBA... Daily Knicks (Maxwell Ogden) —New York Knicks star Carmelo Anthony is celebrating his 33rd birthday on Monday, May 29! Join us in wishing the franchise player a Happy Birthday. Carmelo Anthony has been the face of the New York Knicks for the better part of seven years. He’s led the organization to success it hadn’t experienced in nearly 20 years, and has remained […] New York Knicks: Happy 33rd... Daily Knicks (Maxwell Ogden) —In this edition of the 2017 NBA mock draft, the New York Knicks are ambitiously successful. Who are the Knicks picking in this week’s projections? The New York Knicks are rapidly approaching an event that will make or break Phil Jackson’s tenure as team president. There are a number of intriguing prospects to be found in […] New York Knicks: An Ambitious And Optimistic 2017... Daily Knicks (Maxwell Ogden) —Amidst a flurry of trade rumors, New York Knicks star Carmelo Anthony is turning his attention to training for the 2017-18 NBA season. Carmelo Anthony is approaching an offseason that could end his tenure as the face of the New York Knicks. He’s been the most prominent player along the NBA rumor mill for close to […] New York Knicks: Carmelo Anthony Is Already Training For... Daily Knicks (James O'Connell) —If Dennis Smith is still available at No. 8 overall in the 2017 NBA Draft, the triangle offense can’t be the reason the New York Knicks pass up on him. Dennis Smith Jr. out of North Carolina State is widely regarded as one of the top point guards in the 2017 NBA Draft. His dynamic scoring […] New York Knicks: Triangle Can’t Be An Excuse To Pass on Dennis Smith - Daily... Daily Knicks (Maxwell Ogden) —Phil Jackson trusts few individuals more than he does Clarence Gaines. That trust paid off when Gaines convinced the New York Knicks to draft Kristaps Porzingis. Earlier this year, Alex Kennedy of Basketball Insiders provided a beautiful look into the inner workings of an NBA front office. Although the piece was focused more on the […] New York Knicks: Clarence Gaines Convinced Phil... Daily Knicks (Maxwell Ogden) —If Malik Monk is still on the board at No. 8 overall in the 2017 NBA Draft, the New York Knicks would be wise to take a chance on him. Here are five reasons why. Few prospects in the 2017 NBA Draft are more polarizing and divisive than Kentucky Wildcats star Malik Monk. Despite intriguing […] New York Knicks: 5 Reasons To Select Malik Monk In 2017 NBA Draft - Daily Knicks - Daily... Daily Knicks (El-Nazr McDowell) —The New York Knicks may want to trade Carmelo Anthony, but he’s in control of his own destiny. Is this all an act of futility? Popular discussion of trading Carmelo Anthony has been forcefully encouraged by team president Phil Jackson, and entertained by New York Knicks fans and journalist alike. However, Anthony still holds all the chips in this […] New York Knicks: Is Trading... Daily Knicks (Chris Priczak) —With the 2016-17 NBA D-League season in the books, Daily Knicks takes a look back at the top moments of the Westchester Knicks’ season. Coming off a season where the Westchester Knicks finished with a 28-22 record and made the 2016 playoffs, the Knicks had high hopes for 2016-17 season. Westchester had six returning players […] Westchester Knicks: Top Moments Of The 2016-17... Daily Knicks (Maxwell Ogden) —The New York Knicks are reportedly intrigued by 2017 NBA Draft prospect Malik Monk. Phil Jackson and Steve Mills proved as much by scouting him in person. The New York Knicks should have options at No. 8 overall in the 2017 NBA Draft. Although some of the top prospects in the annual selection process will be […] Knicks Rumors: Phil Jackson Scouted 2017 NBA Draft Prospect Malik Monk - ... Daily Knicks (Maxwell Ogden) —New York Knicks legend Earl Monroe weighed in on the Phil Jackson and Carmelo Anthony fiasco. The Pearl’s take: Anthony did what he was brought in to do. Team president Phil Jackson and franchise player Carmelo Anthony were supposed to work together to save the New York Knicks. Instead, two men who will one day share […] New York Knicks: Earl Monroe Weighs In On Phil Jackson,... Daily Knicks (Maxwell Ogden) —If the New York Knicks succeed in acquiring another lottery pick in the 2017 NBA Draft, then Indiana Hoosiers star OG Anunoby should be near the top of the big board. The New York Knicks will enter the 2017 NBA Draft with the No. 8 overall selection. As trade rumors swirl around Carmelo Anthony, and […] New York Knicks: OG Anunoby Should Be On The 2017 NBA Draft Radar - Daily Knicks ...	{ "pile_set_name": "Pile-CC" }
Q: Remove previous route and add new one I have a application containing a map activity which has plenty of markers from my SQLite database and a polyline connecting those markers. The problem begins when I want to show a route between any clicked marker and my Location. Problem is it works fine and shows the route for the first time but if any other marker is clicked, a new route is generated without removing previous route. I know the problem is the following code. @Override protected void onPostExecute(List<List<HashMap<String, String>>> result) { ArrayList<LatLng> points = new ArrayList<>(); PolylineOptions lineOptions = new PolylineOptions(); for(int i=0;i<result.size();i++){ List<HashMap<String, String>> path = result.get(i); for(int j=0;j<path.size();j++){ HashMap<String,String> point = path.get(j); double lat = Double.parseDouble(point.get("lat")); double lng = Double.parseDouble(point.get("lng")); LatLng position = new LatLng(lat, lng); points.add(position); } lineOptions.addAll(points); lineOptions.width(5); lineOptions.color(Color.WHITE); } // googleMap.clear(); //setMarkersPolyLines(); googleMap.addPolyline(lineOptions); } My efforts till now: Googled it and found a way using polyline.remove(); but the problem is if placed after addPolyline then newly created route is also removed and if placed before that then error comes saying polyline might not be initialised. Tried with if else as if(flag==0){ polyline = googleMap.addPolyline(lineOptions); flag++; } else if(flag>0) polyline.remove(); polyline = googleMap.addPolyline(lineOptions); } but nothing happened. Tried these steps but it causes a glitch/fluctuation kind of thing and also some delay. googleMap.clear(); setMarkersPolyLines(); //setting all my markers again googleMap.addPolyline(lineOptions); Atlast, tried initialising points and lineoptions in the for loop but again might not be initialised error and can't set to null as giving nullPointerException as PolylineOptions can't be set to null. I tried many posts but nothing really was working. Thanks. A: I've modified Josef Adamcik's answer and it should work. boolean isSecond = false; private Polyline lastPolyline; @Override protected void onPostExecute(List<List<HashMap<String, String>>> result) { ArrayList<LatLng> points = new ArrayList<>(); PolylineOptions lineOptions = new PolylineOptions(); for(int i=0;i<result.size();i++){ List<HashMap<String, String>> path = result.get(i); for(int j=0;j<path.size();j++){ HashMap<String,String> point = path.get(j); double lat = Double.parseDouble(point.get("lat")); double lng = Double.parseDouble(point.get("lng")); LatLng position = new LatLng(lat, lng); points.add(position); } lineOptions.addAll(points); lineOptions.width(5); lineOptions.color(Color.WHITE); } if(isSecond) { lastPolyline.remove(); lastPolyline = googleMap.addPolyline(lineOptions); } else { lastPolyline = googleMap.addPolyline(lineOptions); isSecond=true; } }	{ "pile_set_name": "StackExchange" }
In the heart of Richmond Hill this home is located in the Main Street community, which is located within walking distance to Elementary Schools. This 3 bedroom, 2.5 bath offers open floor plan. Laminate wood floors throughout main living area and new paint. Large Family room with gas fire place. Kitchen and eat in breakfast area plus separate dining space. All bedrooms located upstairs plus a loft area. Over-sized Master bedroom with tons of windows to allow lots of natural light. Master bathroom with large soaking tub and separate shower, double vanities. 2 additional guest bedrooms. 2 car garage. Covered Patio space and this home backs up to wooded area. TOTAL MONTHLY PAYMENT 0 Principal+Interest P I *Estimate only SATELLITE VIEW We respect your online privacy and will never spam you. By submitting this form with your telephone number you are consenting for Maureen Bryant to contact you even if your name is on a Federal or State "Do not call List". Listed with The Randy Bocook Real Estate Team The data relating to real estate for sale on this web site comes in part from the Broker Reciprocity Program of the Savannah Multi-List Corporation. All real estate listings are marked with the name of the listing brokers. The broker providing these data believes them to be correct, but advises interested parties to confirm them before relying on them in a purchase decision. First Name:Last Name:Email: Please confirm if you want to receive e-mail updates from and other Diverse Solutions products: I confirm, I would like to receive e-mail updatesI do not want to receive e-mail updatesPhone Number:Password:Confirm Password: Remember me Find Us On Login Reset Password We use cookies to provide you with a better service on our websites. You are free to manage this via your browser setting at any time. To learn more about how we use the cookies, please see our privacy policy.OkPrivacy policy	{ "pile_set_name": "Pile-CC" }
Q: How to remotely check the status of a web application pool with PowerShell? I see a lot of scripts for recycling application pools on a web server running IIS7 but is there a way to check, with PowerShell, that the web application pool is running or stopped? I can't seem to figure out a way to remotely have Get-WebAppPoolState return the status on the Application Pool, and my Google-fu has not been able to come up with a replacement. I can remotely get gwmi to work and recycle or start my app pools but ideally I only want to have to run this if the app pool is actually stopped. Would I need to work this out with PSExec or is there an alternative I can use similar to gwmi and have a one line command to call the app pool on the IIS7 server and give me the status? A: You can use Invoke-Command to invoke the Get-WebAppPoolState cmdlet on the remote machine. $appPoolStatus = Invoke-Command -ComputerName RemoteHostName {Import-Module WebAdministration; Get-WebAppPoolState DefaultAppPool} $appPoolStatus.Value Note that if you are going to use variables defined locally on the calling machine, you will have to treat them according to the rules. This link is an excellent post explaining them: http://blogs.msdn.com/b/powershell/archive/2009/12/29/arguments-for-remote-commands.aspx Example: $appPoolName = "SomeAppPoolName" $appPoolStatus = Invoke-Command -ComputerName RemoteHostName { param($apn) Import-Module WebAdministration; Get-WebAppPoolState $apn} -Args $appPoolName A: You can use this if you want pretty out: Invoke-Command -ComputerName RemoteHostName -ScriptBlock { Get-WebAppPoolState \| % { return @{($_.itemxpath -split ("'"))[1]="$($_.value)" } }}	{ "pile_set_name": "StackExchange" }
1. Field of the Invention The present invention relates to an optical transmission system using an optical fiber cable as a transmission line. 2. Description of the Related Art Optical transmission systems have been developed for large transmission capacity and long span transmission. For accomplishing the large transmission capacity, the increase of bit rate and wavelength division multiplexing system have been studied. For accomplishing the long span transmission, optical amplifiers are used. The optical amplifiers are categorized as for example a post-amplifier that raises the transmission power, a pre-amplifier that raises the sensitivity of received power, and an in-line amplifier that functions as a repeater. These optical amplifiers have been developed as products. With the optical amplifiers, the difference of levels of a received signal and a transmitted signal becomes large and the allowable loss of an optical fiber cable becomes large. On the other hand, with optical amplifiers, the optical input level to the optical fiber cable becomes high. Thus, a new problem called non-linear effect has taken place. As an example, when the level of an optical signal that is input to the optical fiber cable is large (for example, +8 dBm for a dispersion shifted optical fiber cable and +10 dBm or more for a single mode optical fiber cable), a frequency (wavelength) shift takes place at a leading edge and a trailing edge of a pulse of the optical signal due to the optical Kerr effect (the refractive index varies depending on the intensity of light) (this phenomenon is referred to as self phase modulation). In this case, even if the spectral width of an optical signal before the transmission is narrow, the spectral width becomes wide through transmission. In addition, due to the influence of the dispersion of the optical signal on the transmission line, the waveform of the received signal becomes degraded. In other words, the upper limit of the power of transmission optical signal depends on such an influence. Moreover, since the velocity of light that propagates in an optical fiber cable depends on the wavelength thereof, after an optical pulse with a particular wavelength is transmitted through an optical fiber cable, the pulse width may be expanded or compressed. This phenomenon is referred to as chromatic dispersion in optical fiber cable. Thus, after an optical signal is transmitted through an optical fiber cable of an optical transmission system, the waveform of the received signal varies due to the chromatic dispersion. Depending on the degree of the chromatic dispersion, a transmission error takes place. Thus, the transmission distance may be restricted due to the chromatic dispersion. So far, transmission deterioration due to the chromatic dispersion on the optical fiber cable is prevented using a light source with a narrow wavelength width. However, in recent years, due to high bit rate of 10 Gb/s and the non-linear effect of an optical fiber cable, the transmission deterioration cannot be prevented using a light source with a narrow wavelength width. To solve such a problem, an optical transmission system with a dispersion compensation has been used. However, since the cost of the dispersion compensator is high and the dispersion compensation amount varies corresponding to the transmission distance, there need be a variety of products. Thus, it is difficult to use the optical transmission system with a dispersion compensator. In such a conventional technology, as a pre-chirp of the transmitter, a blue chirp (chirping parameter xcex1 less than 0) is used. In addition, a dispersion compensator is placed on the receiver side (between a pre-amplifier and an optical-electrical signal converter (O/E)) (namely, post compensation is performed). However, in this system, since the compensation is inflexibly performed, the loss of the dispersion compensator becomes large. The loss cannot be ignored when the transmission distance becomes long. In addition, since the input level of the optical signal becomes low, the receiver sensitivity degrades. Moreover, since the tolerance of the dispersion compensation amount for proper transmission characteristics is narrow, dispersion compensators should be prepared corresponding to the transmission distance. Thus, many types of products should be prepared. To solve such a problem, a system in which a red chirp (chirping parameter xcex1 greater than 0) is used as a pre-chirp on the transmitter side and dispersion compensators are disposed on both the transmitter side and the receiver side was considered. FIG. 1 shows a basic structure of this system. FIG. 1 is a block diagram showing an outlined structure of a conventional optical transmission system. The optical transmission system shown in FIG. 1 comprises a transmitter 160, a transmission line 164 (composed of an optical fiber cable), and a receiver 165. The transmitter 160 comprises an E/O (electric-optical signal converter) 161, a dispersion compensator 162, and a post-amplifier 163. The E/O 161 converts an electric signal into an NRZ coded optical signal. The post-amplifier 163 amplifies the optical signal and sends the resultant signal to the transmission line 164. The receiver 165 comprises a pre-amplifier 166, a dispersion compensator 167, and an O/E (optical-electric signal converter) 168. The pre-amplifier 166 amplifies weakened light that has been transmitted through the transmission line 164. The dispersion compensator 167 compensates for the dispersion of the optical signal that has been transmitted through the transmission line 164. The O/E 168 converts an optical signal into an electric signal. In the conventional optical transmission system, the transmitter 160 red-chirps an optical signal as a pre-chirp. In addition, the transmitter 160 uses an NRZ coded signal as an optical signal. The dispersion compensator 162 in the transmitter 160 compensates for a predetermined dispersion amount of an optical signal so as to cancel the dispersion of the optical signal propagated on the transmission line 164. The post-amplifier 163 amplifies the intensity of an optical signal so that it can be transmitted for a long distance. The pre-amplifier 166 in the receiver 165 amplifies a weakened optical signal propagated on the transmission line 164 so that the optical signal can be detected. The dispersion compensator 167 adjusts the dispersion compensation amount corresponding to a dispersion amount of the transmission line 164 detected by the receiver 165 so that the receiver 165 can correctly detect the optical signal. Thus, the dispersion compensator 167 in the receiver 165 can adjust the dispersion compensation amount. The O/E 168 converts an optical signal into an electric signal. The O/E 168 sends the received signal to an electric signal processing unit (not shown) disposed downstream thereof so as to demodulate the electric signal and extract data from the optical signal. Thus, in the system shown in FIG. 1, the transmitter 160 red-chirps an optical signal. In addition, both the transmitter 160 and the receiver 165 have respective dispersion compensators. In this compensation system, the dispersion compensation on the transmitter side is effective. The transmitter compresses pulses corresponding to the chirping and the characteristics of the dispersion compensator. Thus, inter-symbol interference due to the increase of the pulse width on the transmission line is alleviated. In addition, since the red-chirping is used, the influence of the non-linear effect (SPM) on the transmission line is canceled. Thus, the deterioration of the waveform of the transmission signal is smaller than that in the case of the blue-chirping. Thus, since the tolerance of the compensation amount is wide, the number of types of dispersion compensators can be reduced. However, as a problem of the system, since the dispersion compensation amount is large, many dispersion compensation optical fiber cables that are expensive should be used. Thus, the cost of the system becomes high. In addition, since the transmitter and the receiver require respective dispersion compensators, the size of the system becomes large. Therefore, an object of the present invention is to provide a technology for accomplishing an apparatus that compensates both the chromatic dispersion of an optical fiber cable and the transmission deterioration of an optical signal due to the non-linear effect, that has sufficient transmission characteristics for a high-power and long-distance optical transmission system, and that is structured at lower cost and in a smaller size than before. An optical transmission system according to the present invention comprises a transmitter that transmits an optical signal, a transmission line that propagates the optical signal, and a receiver that receives the optical signal transmitted through the transmission line. In a high-output-power and high-transmission-rate optical transmission system of which an optical signal propagated in the transmission line is dispersed due to the non-linear effect, the transmitter generates an RZ coded optical signal and transmits the resultant signal. Conventionally, such an optical transmission system with high output power and high transmission rate uses an NRZ coded signal. However, since such a signal is subject to inter-symbol interference, the dispersion compensation amount is large. A dispersion compensator that compensates the dispersion of an optical signal is expensive. In addition, the dispersion compensator requires a space to be disposed. Thus, such a dispersion compensator prevents the cost and size of the apparatus from being reduced. In contrast, according to the present invention, since an RZ coded signal is used, the inter-symbol interference can be suppressed. Thus, the dispersion compensation amount can be reduced. Alternatively, according to the present invention, an optical signal can be transmitted for a longer distance with the same dispersion compensation amount. Thus, the cost and size of the apparatus can be reduced. In addition, although the receiver has a dispersion compensator that compensates the dispersion of an optical signal propagated through the transmission line, the transmitter does not require a dispersion compensator. Thus, the present invention contributes to reducing the size of the transmitter. Moreover, since the transmitter pre-chirps an RZ coded optical signal and transmits the resultant signal, the optical signal can be prevented from being affected by the non-linear effect (that is proportional to the output power of the optical signal) on the transmission line. Thus, the optical signal can be transmitted for a long distance with a small dispersion compensation amount. In the optical transmission system according to the present invention, the dispersion compensator disposed on the receiver side is composed of a plurality of dispersion compensation units each of which has a predetermined or standardized dispersion compensation amount. Thus, when the dispersion compensation amount is adjusted on the receiver side, with a combination of the dispersion compensation units, it is not necessary to prepare a dispersion compensator corresponding to a required dispersion compensation amount. Consequently, according to the present invention, the optical transmission system can compensate for the dispersion of an optical signal simply and inexpensively. These and other objects, features and advantages of the present invention will become more apparent in light of the following detailed description of a best mode embodiment thereof, as illustrated in the accompanying drawings.	{ "pile_set_name": "USPTO Backgrounds" }
using System; using System.Collections.Generic; using System.Linq; using System.Threading.Tasks; using System.Transactions; using InventoryService.Api.Database; using InventoryService.Api.Models; using Microsoft.EntityFrameworkCore; using Microsoft.Extensions.Logging; namespace InventoryService.Api.Services { public class SqlInventoryData : IInventoryData { private readonly InventoryContext context; private readonly ILogger<SqlInventoryData> logger; public SqlInventoryData(InventoryContext context, ILogger<SqlInventoryData> logger) { this.context = context; this.logger = logger; } public async Task<IEnumerable<InventoryItem>> GetInventoryBySkus(IEnumerable<string> skus) { return await context .Inventory .Where(i => skus.Contains(i.Sku)) .ToListAsync() .ConfigureAwait(false); } public async Task<InventoryItem> CreateInventory(string sku, int quantity, DateTime modified) { var item = new InventoryItem { Sku = sku, Quantity = quantity, Modified = modified }; context.Inventory.Add(item); await context.SaveChangesAsync(); return item; } public async Task<InventoryItem> UpdateInventory(string sku, int quantityChanged) { using (var scope = new TransactionScope(TransactionScopeAsyncFlowOption.Enabled)) { var item = await context.Inventory.FindAsync(sku); if (item != null) { item.Quantity += quantityChanged; var averageQuantity = quantityChanged / item.Quantity; // should an exception if 0 (for app insights demo) item.Modified = DateTime.Now; await context.SaveChangesAsync(); scope.Complete(); return item; } else { logger.LogError("Error updating sku. Sku '{sku}' not found.", sku); throw new ArgumentException("Sku not found"); } } } } }	{ "pile_set_name": "Github" }
Memory-Efficient Search Trees for Database Management Systems [pdf] - ngaut http://reports-archive.adm.cs.cmu.edu/anon/2020/CMU-CS-20-101.pdf ====== willvarfar A lot to digest. Presumably the compression schemes outlined in the paper would benefit columns generally, and not just keys, and would have a positive impact on row-size which would in turn benefit general performance? One short-string-compression-library to compare with might be [https://github.com/antirez/smaz](https://github.com/antirez/smaz) by the Antirez, the author of redis. In the last decade Tokudb and then MyRocks showed how to do a fast storage engine for data too big to fit in traditional RDBMS. They are multi-level, they do page-level compression etc. And yet there is still so many easy wins yet to be had. Generally, databases are completely inefficient and there is just so much low- hanging fruit; if the team size working on e.g. myrocks could be doubled, and tasked with looking at the inefficiencies in the server as well as the storage engine, things might change. I have a list in my head of the various really- promising-ideas that databases don't actually do: * linux doesn't have a syscall batching system, but if it did, the number of context switches would be cut down dramatically. Research in 2010 [https://www.usenix.org/legacy/events/osdi10/tech/full_papers...](https://www.usenix.org/legacy/events/osdi10/tech/full_papers/Soares.pdf) proved this and it wouldn't just be databases that benefit. These days context switching is more expensive than ever. * database engines all use blocking io. Finally io_uring offers workable async io and that would benefit database storage engines immensely. See [https://fosdem.org/2020/schedule/event/rust_techniques_sled/](https://fosdem.org/2020/schedule/event/rust_techniques_sled/) * tokudb showed that simply not tracking the affected row count could speed things up massively (tokudb called it NOAR) * query engines often don't handle things that a few more lines of code would handle efficiently. I've got some tables with big compound keys and often do prefix searches in them, and why isn't mysql evaluating constraints that it can against the other columns in the key before dereferencing the row? Arrgh. Dumb dumb dumb. Etc. ~~~ qaq "database engines all use blocking io" Well sled is using io_uring ~~~ samatman probably why that paragraph had a link to a video titled "sled and rio: modern database engineering with io_uring"... ~~~ qaq which was my point :) ------ derefr I've always wondered why I haven't seen a DBMS built as a unikernel. A DBMS is already a "managed runtime" for data, with its own memory allocator, scheduler, filesystem (in some sense), etc. And you're _almost_ always going to want to run a DBMS "workload" on its own dedicated hardware/VM, anyway, for predictability. So why not just take that set of DBMS services and put them in ring-0, where they won't need any context-switch overhead, will have fine-grained control over their own queuing for kernel resources, and where they can pass data structures by reference all the way from the network to the disk and back? In Linux, we already have Open-iSCSI, which just has the control plane in userspace, while the data plane is entirely a Linux kernel service, gaining it all these advantages. This architecture works very well there; I'm unclear on why others attempting to provide the higher-level "data-management solutions", with the same high-throughput/low-latency requirements, haven't copied it. ~~~ aratno Sounds like you would be interested in this paper on TabulaROSA: [https://arxiv.org/pdf/1807.05308.pdf](https://arxiv.org/pdf/1807.05308.pdf) ------ jandrewrogers This is a good paper and I appreciate the holistic focus on cache efficiency, an area where multiple orders of magnitude of performance improvement are often easily attainable compared to many common implementations. However, it also highlights the gap between academic literature and the state-of-the-art in database engine design. For example, adaptive succinct indexing structures have been used for at least a decade in closed source databases. Structures similar to the ideas presented in the paper have been reduced to practice in real systems for a long time. Last month I delivered yet another database engine, benchmarked against the best open source comparables, which provides a rough but concrete example of the gap: The designed memory:storage ratio was 1:1000, an order of magnitude higher than even the 1:100 ratio mentioned as aggressive in the paper. In fairness, my prior systems were designed much closer to 1:100 ratio and it used new CS research to significantly extend the ratio without materially sacrificing performance. For data models with fairly complex indexing requirements, insertion performance was >100x(!) the best open source comparables. A large part of this performance is due to dramatic improvements in cache efficiency that are not even particularly novel -- the gains attributable to improved cache efficiency in the paper are eminently believable. The data-to- index ratio in the above is around a million-to-one, small enough to fit in CPU cache for many TB scale data models. The high data-to-index ratio is largely attributable to using search structures that forego total order and balancing, which enables dramatic improvements in succinctness with minimal reductions in selectivity. The other major contributor to performance is scheduler design, which wasn't really touched on in the paper and is largely ignored entirely in open source databases. tl;dr: current open source database engine designs leave a massive amount of performance on the table due to very poor cache efficiency, and this paper correctly touches on some of the ways this is materially improved in closed source database engines. ~~~ willvarfar Can you give names of closed-source database engines that have these kinds of performance improvements? I mean, the mainstream RDBMS like Oracle, DB2 etc don't seem to be ahead of the open source databases; they are all stagnant too! ~~~ jandrewrogers Databases are severely constrained by the architecture choices from when they were designed, you can't back port modern database architecture and computer science to e.g. an Oracle or DB2. To integrate new computer science advances you often need to write a new kernel from first principles. I sunset the designs I license to companies every several years, starting over from a clean sheet. Most new high-performance database engines are intended to give the developing company a new qualitative uplift in capability, scale, or operational efficiency. No one sells public licenses these days. You've heard of the organizations that are buying building these semi-bespoke database engines but they are intended for internal use only. The reason no one sells these capabilities as a product anymore is pragmatic: it is extremely expensive to design a database engine for general public consumption and the economics are difficult to justify as an investment. But many large companies are willing to pay many millions of dollars for a narrowly focused database capabilities, and the reduced scope makes the development cost more palatable. ~~~ eternalban Was skimming at your Space Curve writeup [1] and your mention of discreet internal components caught my eye. Are you open to expanding a bit on this statement: "Discrete topology internals largely obviate secondary indexing" [1]: [https://www.jandrewrogers.com/2015/10/08/spacecurve/](https://www.jandrewrogers.com/2015/10/08/spacecurve/) ~~~ jandrewrogers Secondary indexing is a hack to address the reality that most indexing algorithms can only represent a single type of relationship efficiently and typically only in a single dimension. This is not a law of the universe, it is just how our algorithms tend to work. If you could eliminate secondary indexing without sacrificing selectivity, it would be a massive win for performance and scalability. However, this would require a single indexing algorithm for complex data models that preserved an arbitrary mix of relational, time-series, spatial, graph, etc relationships for searches and joins. To make this work in a practical database engine, you can't index the data model per se but you can make it work by indexing a _moduli space_ into which arbitrary data models can be mapped. These tend to naturally expose the topological structure of the underlying data model for computational purposes even though you are not computing on the data model per se. Designing very general moduli spaces for database purposes is non-trivial and, to make matters worse, they are pathologically incompatible with typical surrounding database infrastructure once you figure out how to construct them. But you can use the exposed topology to execute complex searches and joins on the underlying data model. None of my database engines use secondary indexing at all, hence the excellent scaling and write performance, even for complex mixed-mode data models. A decade ago the representations were pretty brittle and limited because I didn't know how to express many things, but these days I know how to elegantly express just about every common data model. ~~~ eternalban Thanks! > a moduli space into which arbitrary data models can be mapped Very interesting. Somehow reminds me of using latices for deterministic concurrency. Is this a topic that is discussed in public literature or an innovation of yours? Love to learn more about this. ~~~ jandrewrogers The work is mostly mine but I've had collaborators for some of the research over the years. I accidentally invented it many years ago when I discovered an unorthodox but elegant solution to an algorithm problem which had stymied researchers for decades (and which I needed to solve for a specific application). Some months later, a research group I was working with were convinced that the unusual algorithm construction might be applicable to an unrelated algorithm problem they had been working on. Six weeks later I had solved their problem too by extending the concepts developed for my original algorithm. By that point I realized that while those two very different algorithms were cool, the half-baked computer science I had developed to construct them was even cooler. I spent the next decade fleshing out, generalizing, and extending the scope of the computer science while figuring out how to efficiently express that theory in practical software (which is not trivial). While I wrote quite a few papers on this computer science many years ago when it was new, the distribution was required to be non-public. I sporadically teach bits of it but writing up hundreds of pages of old research in my spare time is a lot less fun than working on my backlog of interesting computer science projects. ------ alecco Note by compression they mean keeping internal blocks closer to full. It looks like a good thesis and advisors are reputable. But this comes with a trade-off. As blocks are full, inserts trigger more often a cascade effect. Batching inserts helps but once you need to apply the batch that could take a long time to rebalance potentially the whole tree. This adds a fat tail to insert times. But in many read-heavy scenarios it is a good trade-off. ~~~ dgacmu There was an aspect of that in the first part of the thesis, but the rest has techniques that are independent. You can roughly break the thesis down by paper: * Hybrid Indexes (a read-only, full-block kinda thing where you have to handle inserts by using a second read-write tree) * SuRF, a succinct range filter data structure * Order-Preserving Key Compression for In-Memory Search Trees Each of them can be used independent of the others, or combined. You can find two of those papers on Huanchen's web page: [http://www.cs.cmu.edu/~huanche1/](http://www.cs.cmu.edu/~huanche1/) the third is to-appear, but you can find a preprint on arxiv: [https://arxiv.org/abs/2003.02391](https://arxiv.org/abs/2003.02391) ~~~ alecco Excellent. Great job! ------ scandum How does it perform against googlebtree? [https://www.tommyds.it/doc/benchmark](https://www.tommyds.it/doc/benchmark) ------ 7532yahoogmail Off topic to OPs paper however consider the case of volt-db an all in memory SQL db with replication. In the sales'y' write speed was written down to less locks, latches, disk I/O. But somewhere else I read that a big culprit in fact isn't that: it's formatting data to be written to disk then decomposing a disk block back into memory for use. All memory dbs avoid that. Thoughts ? ------ 7532yahoogmail Working my way through paper. Looks very cool. And practical ... It's also exceptionally well written. It's clear. Nice job ------ rini17 Only read the conclusion and it's not mentioned there: did they consider locality and thus cache/paging misses?	{ "pile_set_name": "HackerNews" }
There are many ways of extracting water from air but many of them struggling with efficiency and that they demand a lot of energy.	{ "pile_set_name": "USPTO Backgrounds" }
Deputy Chief Justice of South Africa The Deputy Chief Justice of South Africa is a judge in the Constitutional Court of South Africa and the second-highest judicial post in the Republic of South Africa, after the Chief Justice. The post, originally called "Deputy President of the Constitutional Court", was created in September 1995 by the Constitution of the Republic of South Africa Second Amendment Act, 1995, which was an amendment to the Interim Constitution. The position was retained by the final Constitution which came into force in February 1997. In November 2001 the Sixth Amendment of the Constitution of South Africa restructured the judiciary, and the post was renamed to "Deputy Chief Justice". The first Deputy President of the Constitutional Court was Ismail Mahomed. In 1997 he became Chief Justice, and was replaced by Pius Langa, who continued as Deputy Chief Justice after 2001. Justice Langa was elevated to Chief Justice in 2005, and succeeded by Dikgang Moseneke. Moseneke retired on 20 May 2016. List of Deputy Chief Justices Ismail Mahomed (1995 – 1997; as Deputy President of the Constitutional Court) Pius Langa (2001 – 2005) Dikgang Moseneke (2005 – 2016) Bess Nkabinde (2016 – 2017) Raymond Zondo (June 2017 - present) References External links Constitutional Court of South Africa Category:Judiciary of South Africa Category:Constitutional Court of South Africa	{ "pile_set_name": "Wikipedia (en)" }
Paint pads are becoming increasingly popular for applying paint due to a number of factors, including the evenness with which a layer of paint or other coating can be applied on flat surfaces. Such pads can also bring paint very close to an interior corner formed by two meeting surfaces or planes, but, to date, a good system for applying a very even coating to such interior junctions or corners has not appeared on the market in a paint pad which can paint flat surfaces and such interior corners with equal ease. Likewise, a paint pad which can paint exterior corners and flat surfaces with equal facility has not been known. A number of proposals have been made for paint pads which address these tasks but none can be described as having achieved general acceptance in the sense that the same pad may be used during one painting job for painting flat surfaces, interior corners and exterior corners. Attempts by prior art workers to achieve one or more of these painting conditions are illustrated in U.S. Pat. Nos. 3,464,079, 3,713,744, 3,728,755, 3,051,977 and 4,674,144. Of the products illustrated in said patents, the '079 and '144 patents show pads useful only for painting exterior corners, and the '744 and '755 and '977 patents disclose applicators which are incapable of painting exterior corners. Of particular significance is that none of the devices of the above prior art are capable of reorientation during use in the sense of adaptation to a different painting condition from paint loading to paint loading without breaking the rhythm of the paint applicator user. Further, none of the known prior devices are applicable to surface junctions having angles greater or lesser than a right angle, as well as right angle junctions. Thus there exists a need for a pad-type universal paint applicator which can apply paint or other coating to flat surfaces, interior corners and exterior corners with equal facility by using only hand applied pressure exerted on the paint applicator during the painting operation so that the painting rhythm of the user is uninterrupted.	{ "pile_set_name": "USPTO Backgrounds" }
Crown Crown may refer to: Currency Currencies Crown (currency) Contemporary currencies Czech koruna Danish krone Faroese króna Icelandic króna Norwegian krone Swedish krona Historical currencies Austrian krone Austro-Hungarian krone Bohemian and Moravian koruna Czechoslovak koruna Estonian kroon Hungarian korona Slovak koruna Historical coins Crown (Australian coin) Crown (British coin), a heavy silver coin Crown (English coin), an English coin introduced as part of King Henry VIII's monetary reform of 1526 Crown, the French Écu Crown, the 5 Marks coin of the German gold mark Monarchy and government Crown (headgear), often an emblem of a monarchy, a monarch's government, or items endorsed by it Crown (heraldry), a depiction of a crown used in heraldry Crown, by metonymy, the term for a monarch or the form of government of a monarchy The Crown, the legal embodiment of monarchical governance in a realm of the Commonwealth of Nations Arts, entertainment, and media Music Groups Carolina Crown Drum and Bugle Corps, a junior drum corps from South Carolina Crown the Empire, an American metalcore band Crowns (band), an English folk punk band The Crown (band), a Swedish death/thrash band Albums and songs The Crown (album), a 2014 album by Z-Ro "Crown" (Azealia Banks song), 2017 "Crown" (Stormzy song), 2019 "Crown", a song by Camila Cabello and Grey from the 2017 album Bright: The Album "Crown", a song by Kelly Rowland, 2019 "Crown", a song by TXT, 2019 "The Crown", a song by Gary Byrd and the GB Experience, 1983 Other uses in arts, entertainment, and media Crown (manga) The Crown (TV series), about Queen Elizabeth II Brands and enterprises Crown (St. Paul's Churchyard), a historical bookseller in London Crown Equipment Corporation, an American manufacturer of forklifts Crown International (Crown Audio), an American manufacturer of audio electronics Crown International Pictures, a defunct American independent film studio and distribution company Crown Lager, an Australian beer Crown Liquor Saloon, a pub in Belfast Crown, an imprint of Crown Publishing Group Crown Royal, a Canadian whiskey Crowns brand cigarettes, produced by Commonwealth Brands Geography Crown, Inverness, an area situated beside the city centre of Inverness Crown, Missouri, a community in the United States Crown Wetlands, Cayman Islands The Crown (mountain), a mountain in the Karakoram of China Motor vehicles Crown (automobile), an automobile built in Detroit, MI, in 1905 Crown Pacer, a 1978 show car by American Motors; See AMC Pacer Ford Crown Victoria Ford LTD Crown Victoria Toyota Crown, an automobile built for the Japanese and other select Asian markets Science and healthcare Dentistry Crown (dentistry), a dental treatment Crown (tooth), a portion of a tooth Life sciences Crown (anatomy), the top of the head Crown (botany), the branching leaf-bearing portion of a tree Crown group, in phylogenetics Hair whorl, also known as a crown Other uses in science and healthcare Crown ether, in chemistry Crown graph, in graph theory Ships Crown (1793 ship) Crown, a cruise ship later renamed MS Albatros HMS Crown, Royal Navy ships Other uses Crown, the top or hinge of a bell Crown, the topmost part of a hat Crown, the cross-sectional shape of a road surface Crown, a whole turkey with the legs and wings removed to produce a joint of white meat Crown, the grooved knob or dial on the outside of a watch case See also Ancient Roman awards for individuals' starring roles in warfare: For rescues in battle: Civic Crown, of a citizen Grass Crown, of a city For offensive tactical initiative: Camp crown, in penetrating camp Mural crown, in scaling city walls Naval crown, in boarding enemy ship	{ "pile_set_name": "Wikipedia (en)" }
Electronic devices often contain displays. A display may have an active area with pixels that display images for a user and an inactive area alongside the active area. A layer of glass may serve as a protective display cover layer. The layer of glass may overlap the active area and the inactive area. To hide internal components from view, the inner surface of the inactive area may be covered with an opaque masking layer such as a layer of black ink. Windows in the display cover layer may be formed from openings in the opaque masking layer. Light-sensitive components may be aligned with the windows. For example, an ambient light sensor may be aligned with a window in a display. To improve the outward appearance of the display cover layer in the inactive area, ambient light sensor windows may be covered with coatings of dark ink. Dark ink coatings for ambient light sensor windows are sometimes referred to as ambient light sensor inks. The presence of the ambient light sensor ink on an ambient light sensor will darken the outward appearance of the ambient light sensor window and thereby help visually blend the ambient light sensor window with surrounding portions of the layer of black ink in the inactive area. At the same time, the ambient light sensor ink will be sufficiently transparent to allow ambient light to reach the ambient light sensor that is aligned with the ambient light sensor window. Although the presence of ambient light sensor ink on an ambient light sensor window may help improve device aesthetics, the presence of the ambient light sensor ink may introduce non-ideal characteristics to an ambient light sensor system. For example, ambient light sensor readings may vary as a function of the angle of incidence of incoming ambient light with respect to the ambient light sensor system.	{ "pile_set_name": "USPTO Backgrounds" }
Features a peep-sight eliminating system called RTL (Retina Lock Technology), RTL helps you to shoot better & more accurately by quickly correcting your form before each shot using a red dot and a bla... Offers a new 2" housing for optimal view of your target, contains T.C.V. (True Center Vision) which provides a perfect circular picture--even when viewed slightly off center, also features A.F.T. (Arm...	{ "pile_set_name": "Pile-CC" }
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Q: How to find Bootloader Load Address? I've followed the tutorial found at: http://www.devttys0.com/2011/05/reverse-engineering-firmware-linksys-wag120n/ I've loaded the uboot image into IDA, but I'm not sure how to determine the load address. I've looked through start.S for a general idea of how things work, but was unable to apply that when looking at the image. I found another tutorial describing how to determine the load address (https://sviehb.wordpress.com/2011/09/09/reverse-engineering-an-obfuscated-firmware-image-e02-analysis/) but could not find the corresponding memory address of the .bss initialization loop in the uboot image. Any help would be greatly appreciated! If you have any tips on determining the load address that would be awesome too. Thanks A: Download link: WAG120N Downloads Firmware binary: $ md5sum WAG120N-EU-ANNEXB-ETSI-1.00.19-code.bin 52d6fa830e31ff96289f8aa41ac713af WAG120N-EU-ANNEXB-ETSI-1.00.19-code.bin Version: Annex B - Version: 1.00.19 (ETSI) Latest Date: 11/17/2014 Signature scan output: $ binwalk WAG120N-EU-ANNEXB-ETSI-1.00.19-code.bin DECIMAL HEXADECIMAL DESCRIPTION -------------------------------------------------------------------------------- 9660 0x25BC U-Boot version string, "U-Boot 1.1.5-2.0 (Jul 22 2009 - 14:05:28)" 9708 0x25EC CRC32 polynomial table, big endian 11012 0x2B04 uImage header, header size: 64 bytes, header CRC: 0xF5170888, created: 2009-07-22 06:05:29, image size: 47540 bytes, Data Address: 0x80400000, Entry Point: 0x80400000, data CRC: 0x84EF8694, OS: Linux, CPU: MIPS, image type: Firmware Image, compression type: lzma, image name: "u-boot image" 11076 0x2B44 LZMA compressed data, properties: 0x5D, dictionary size: 8388608 bytes, uncompressed size: 147212 bytes 65434 0xFF9A Sercomm firmware signature, version control: 1, download control: 256, hardware ID: "YQZ", hardware version: 0x0, firmware version: 0x9, starting code segment: 0x100, code size: 0x7300 65497 0xFFD9 Sercomm firmware signature, version control: 0, download control: 0, hardware ID: "", hardware version: 0x0, firmware version: 0x2700, starting code segment: 0x1A9C, code size: 0x3D0 72028 0x1195C Sercomm firmware signature, version control: 29184, download control: 24933, hardware ID: "d ok..!!", hardware version: 0x7266, firmware version: 0x2578, starting code segment: 0xA78, code size: 0x0 196608 0x30000 uImage header, header size: 64 bytes, header CRC: 0xED45C533, created: 2014-11-04 09:41:33, image size: 577083 bytes, Data Address: 0x80002000, Entry Point: 0x801B2040, data CRC: 0x5AFA7402, OS: Linux, CPU: MIPS, image type: OS Kernel Image, compression type: lzma, image name: "MIPS Linux-2.4.31-Amazon_SE-3.6.]" 196672 0x30040 LZMA compressed data, properties: 0x5D, dictionary size: 8388608 bytes, uncompressed size: 1986560 bytes 851968 0xD0000 Squashfs filesystem, big endian, lzma compression, version 2.1, size: 2991870 bytes, 748 inodes, blocksize: 65536 bytes, created: 2014-11-04 09:42:21 According to the signature scan, the u-boot image is of image type: Firmware Image and data address and entry point is 0x80400000. How should this information be interpreted? Let us begin with a description of U-Boot image formats: From include/image.h: On line 230: * "Firmware Images" are binary images containing firmware (like * U-Boot or FPGA images) which usually will be programmed to * flash memory. The image header: /* * Legacy format image header, * all data in network byte order (aka natural aka bigendian). / typedef struct image_header { __be32 ih_magic; / Image Header Magic Number / __be32 ih_hcrc; / Image Header CRC Checksum / __be32 ih_time; / Image Creation Timestamp / __be32 ih_size; / Image Data Size / __be32 ih_load; / Data Load Address / __be32 ih_ep; / Entry Point Address / __be32 ih_dcrc; / Image Data CRC Checksum / uint8_t ih_os; / Operating System / uint8_t ih_arch; / CPU architecture / uint8_t ih_type; / Image Type / uint8_t ih_comp; / Compression Type / uint8_t ih_name[IH_NMLEN]; / Image Name / } image_header_t; Image info: typedef struct image_info { ulong start, end; / start/end of blob / ulong image_start, image_len; / start of image within blob, len of image / ulong load; / load addr for the image / uint8_t comp, type, os; / compression, type of image, os type / uint8_t arch; / CPU architecture */ } image_info_t; Information about the load address is stored in the uImage header and this is what is output in a signature scan by binwalk. In this case it is 0x8040000. see also: Reverse Engineering MIPS Bootloader MIPS Address Space Reverse Engineering VxWorks Firmware: WRT54Gv8 Unpacking and repacking U-Boot uImage files A Handy U-Boot Trick MIPS Bootstrapping	{ "pile_set_name": "StackExchange" }
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Q: what is the best way to compare two complex java object and generate event depending upon comparision I have a requirement to compare two complex object, e:g Policy{ Private Vehicle-information info1; private Driver-information info2; ... } I have two populated instance of this class. I want to compare those instance and depending upon difference I need to show them in UI marked in colors using some flag. What is the best way to compare these objects. Can we achieve it using XML because java code will be complex. A: Override the equals() and hashCode() method in your Policy class. Then you can check for equality like: if(object1.equals(object2)) { // do something } Implement Comparable and override the compareTo() method if you need to order the objects.	{ "pile_set_name": "StackExchange" }
Space anomalies, missing permanent teeth and orthodontic treatment. Statistical association of crowding and spacing with age, sex, orthodontic treatment and extractions finds a tendency for more maxillary posterior spacing in males and more lower anterior spacing in females. Extractions were also associated with spacing. No association was found between spacing and orthodontic treatment.	{ "pile_set_name": "PubMed Abstracts" }
Introduction {#s1} ============ Genome-wide association studies (GWAS) have identified thousands of genetic variants associated with hundreds of complex human diseases. Most disease variants are located in noncoding regions (Welter et al., [@B24]), the functions of which are difficult to interpret. Several studies (Meyer et al., [@B14]; Maurano et al., [@B13]) have shown that disease variants are enriched in gene regulatory regions and that they may affect phenotypes at the regulatory level (Verlaan et al., [@B23]; Petronis, [@B16]; Stitzel et al., [@B22]; Schödel et al., [@B20]; French et al., [@B5]; Sharma et al., [@B21]). In addition, disease variants are likely to affect gene regulation and phenotypes in a cell-type-specific manner (Fu et al., [@B6]; Hardison, [@B7]; Rhie et al., [@B18]). Using massively parallel sequencing technologies, a plethora of data sets have been generated on a wide collection of functional marks in the human genome in many cell lines and primary ex vivo tissues. A major challenge is how to integrate these functional data in multiple cell types to pinpoint disease-causal variants and understand their molecular and organismal effects in a cell-type-specific context (Edwards et al., [@B1]; Kircher et al., [@B11]). While many methods have used functional annotations to prioritize disease-causal variants (Pickrell, [@B17]; Farh et al., [@B4]; Kichaev and Pasaniuc, [@B10]; Li and Kellis, [@B12]), they have not considered the combinatorial effects of functional elements in different cell types for prediction. The most commonly used approach is based on linear models, where functional data on different epigenomic marks in one or more cell types are used as predictors in a regression model, and the GWAS p-values or the known disease risk variants are used as responses. There is an alternative approach using likelihood-based methods, but these methods simply add the likelihoods calculated from each cell type or each category of annotation to compute a total score for each genetic variant, and then use the total score to prioritize disease variants. This is equivalent to an additive model but ignores correlations between different annotations. There are two major challenges in detecting and utilizing combinatorial epigenomic patterns across cell types for GWAS prediction. First, functional elements inferred in each cell type separately are subject to annotation errors (Roadmap Epigenomics Consortium). When compared across cell types, they will create a large number of spurious combinations of epigenomic patterns with low frequencies, which can substantially reduce the predictive power. Second, the number of possible combinations of functional annotations across cell types grows rapidly with the number of distinct functional elements and the number of cell types involved. Naively including all combinations in one model will over-fit the data and will not produce reliable results, owing to strong correlation between the combinations. For instance, with hundreds of cell types studied in the ENCODE (Encode Project Consortium, [@B2]) and Roadmap Epigenomics (Roadmap Epigenomics Consortium et al., [@B19]) projects, and tens of epigenetic states inferred in each cell type (Ernst and Kellis, [@B3]), the number of potential predictors to be included in a model can easily become intractable, even when just considering pairwise interactions. Existing studies have therefore only used either a subset of cell types most relevant to disease or a linear model across cell types for predicting disease variants (Li and Kellis, [@B12]). In this work, we investigate whether combinatorial patterns of epigenomic data across different cell types can improve the power to predict disease variants. Using the 111 cell types from the Roadmap Epigenomics project and 16 ENCODE tier 1 and 2 cell types, we first apply IDEAS (Zhang et al., [@B25]) to re-annotate functional elements in the 127 epigenomes. IDEAS is a two-dimensional genome segmentation method that identifies de novo functional elements from multivariate epigenetic marks along the genome and across multiple cell types simultaneously. The IDEAS method is distinct from existing genome segmentation methods in that it borrows information both along the genome and across cell types, which leads to a gain in power because different cell types share the same underlying DNA sequences. As a result, IDEAS can produce more accurate and consistent functional annotations than other methods. Using the functional annotations as input, we next develop a Bayesian algorithm for de novo identification of distinct and recurring patterns of epigenome partition patterns in the whole genome. Each pattern of epigenome partitions represents a distinct nonlinear relationship between functional elements across cell types, where the functional elements in the cell types within the same partition have the same distribution, and thus captures cell-type specificity. Hereinafter, we refer to a specific configuration of epigenome partition as a CSP (cell-type-specificity pattern). Finally, we calculate enrichment scores of functional elements within each CSP and use both the CSP and epigenetic state enrichment scores as predictors for prioritizing disease variants. Notably, we do not make assumptions on the relationships between each cell type and the disease, since such information is often unknown. We evaluate the proposed method on 532 complex traits in the GWAS Catalog (Welter et al., [@B24]). We show that in a large number of complex traits, the disease variants are enriched in active functional elements, with this enrichment frequently being cell-type-specific and interpretable with respect to each trait. By comparing our results with those of linear models, we further show that incorporating nonlinear epigenetic CSPs can indeed improve the accuracy for predicting disease variants compared with the use of either a single best-matched cell type or all cell types in an additive way. Materials and methods {#s2} ===================== Joint genome segmentation of the 127 epigenomes ----------------------------------------------- We downloaded the p-value tracks of five histone marks (H3k4me3, H3k4me1, H3k36me3, H3k27me3, and H3k9me3) in 111 epigenomes from the NIH Roadmap Epigenomics project and 16 epigenomes from the ENCODE project. These five histone marks were the only marks commonly generated in all of the 127 epigenomes and were used by the Roadmap Epigenomics consortium to produce the first functional map in the 127 epigenomes. The p-value tracks of histone marks were calculated against the input data within the same cell types, thereby removing cell-type-specific bias and enabling comparison across cell types. We used the average log p-values per 200 bp window for each histone mark as input; this is the same window size as was used by the Roadmap Epigenomics Consortium and is appropriate for the wide spread of signals in histone marks. The data matrix contained 13,844,320 rows and 635 columns, consisting of 8.8 billion observations in total. All data were mapped to hg19. We ran IDEAS (Zhang et al., [@B25]) to segment the 127 epigenomes jointly, which assigned epigenetic states to 200 bp sliding windows in each cell type, capturing the distinct combinatorial patterns of the five histone marks. We first ran IDEAS on chromosome 1, which produced a 25-state model. We then combined chromosome 1 with each of the other chromosomes and re-ran IDEAS, keeping the segmentation results of chromosome 1 unchanged. As a result, all other chromosomes were segmented conditionally independently, given chromosome 1. Our full model-based inference of functional elements in all epigenomes produced homogeneous and position-wise comparable state assignments across the 127 epigenomes, which was ideal for the proposed task of detecting position-wise CSPs. The whole-genome tracks of segmentations for the 25-state model can be accessed in the UCSC genome browser via a hub link to <http://bx.psu.edu/~yuzhang/hub.txt>. Detecting epigenetic cell-type specificity ------------------------------------------ We have developed a Bayesian method to identify recurring CSPs from the IDEAS segmentation. Let X~·j~ = {X~1,\ j~, ..., X~N,j~} denote the states assigned to N epigenomes at positions j = 1, ..., L, where X~i,j~ = 1, ..., S denotes the state assigned to the ith epigenome at the jth position. We want to partition the N epigenomes into K groups at each position, where some groups may be empty, such that within each group the epigenomes have a common and position-dependent distribution of epigenetic states. We assume that the whole genome has C distinct CSPs, denoted by Ω = {Ω~1~, ..., Ω~C~}. Each CSP specifies how the epigenomes are assigned to K groups. We further assume that each CSP occurs with probability p~c~ independently at each position, and we denote by M~j~ = 1, ..., C the CSP at the jth position. We express the probability function as P ( Ω , M \\| X ) ∝ P ( Ω , M , X ) = Pr ( X \\| Ω , M ) Pr ( Ω , M ) = ∏ j p M j Pr ( X · j \\| Ω M j ) ∏ c = 1 C Pr ( Ω c ) where p~Mj~ denotes the prior probability of CSP M~j~, Pr(X~·j~\\|Ω~M~j~~) denotes the state distribution function given Ω~M~j~~ at position j, and Pr(Ω~c~) denotes the prior distribution of epigenome partitions in Ω~c~. We assume a multinomial distribution for the states within each group of epigenomes in each CSP, with position-specific distribution parameters. Let n~kjs~ denote the number of states s observed in the kth group of epigenomes in Ω~M~j~~ at position j. Using the Dirichlet($\overset{\rightharpoonup}{a}$) prior for multinomial distributions, we obtain Pr ( X · j \\| Ω M j ) = ∏ k = 1 K ( Γ ( \\| α ⇀ \\| ) ∏ s = 1 S Γ ( α s ) ∏ s = 1 S Γ ( n k j s \+ α s ) Γ ( \\| n ⇀ k j \\| \+ \\| α ⇀ \\| ) ) where $\overset{\rightharpoonup}{a} = {({a_{1},\ldots,a_{S}})}$ is set as the genome-wide proportion of each epigenetic state in all epigenomes and multiplied by 5, and \\|·\\| denotes the sum of all elements in a vector. Similarly, we assume that each epigenome follows a multinomial distribution to be assigned to the K groups in Ω~c~. Let m~kc~ denote the number of epigenomes assigned to the kth group in Ω~c~. Using the Dirichlet($\overset{\rightharpoonup}{1}$) prior, we express Pr(Ω~c~) as Pr ( Ω c ) = Γ ( K ) ∏ k = 1 K Γ ( m k c \+ 1 ) Γ ( \\| m ⇀ k c \\| \+ K ) Given the CSP index variable {M~j~}, we do not have to infer the parameters p~M~j~~ in (1). Instead, denoting by o~1~, ..., o~C~ the count of each CSP in the genome, we again assume a Dirichlet($\overset{\rightharpoonup}{1}$) prior to p~M~j~~ and marginalize it out to obtain the final form of our model: P ( Ω , M \\| X ) ∝ ( ∏ j ∏ k = 1 K Γ ( \\| α ⇀ \\| ) ∏ s = 1 S Γ ( α s ) ∏ s = 1 S Γ ( n k j s \+ α s ) Γ ( \\| n ⇀ k j \\| \+ \\| α ⇀ \\| ) ) Γ ( C ) Γ ( \\| o ⇀ \\| \+ C ) ∏ c = 1 C ( Γ ( o c \+ C ) Γ ( K ) ∏ k = 1 K Γ ( m k c \+ 1 ) Γ ( \\| m ⇀ k c \\| \+ K ) ) Model fitting ------------- Starting from random initialization, we iteratively updated the CSP index {M~j~} and the epigenome group assignment, denoted by $\left\{ I_{k}^{c} \right\}$, in each CSP. Given {M~j~} and $\left\{ I_{k}^{c} \right\}$, all other variables in our model were deterministic. We updated {M~j~} at each position and $\left\{ I_{k}^{c} \right\}$ for each epigenome in the cth CSP by conditioning on the current values of all other variables. Since {M~j~} and $\left\{ I_{k}^{c} \right\}$ were integer-valued, we enumerated all possible values and calculated the corresponding likelihoods from the model (4). We then updated the model by maximization. We used simulated annealing in the first 50 iterations with an initial temperature set at 5 to alleviate local mode problems. We set the total number of CSPs C = 50 and the number of groups K = 5 per CSP. Although these hyper-parameters were fixed, some CSPs and their epigenome groups did not have instances in the data, since our Bayesian model penalized larger models when smaller models were sufficient to explain the data. To reduce computational cost, we used 5% randomly selected genome to train the model (4), which yielded 48 distinct CSPs. Except for the constitutive CSP, where all epigenomes were assigned into one group, the other 47 CSPs assigned 127 epigenomes into two or three groups. Patterns enriched in GWAS variants ---------------------------------- The risk variants of a trait may fall into two disjoint categories: (1) variants enriched or depleted at loci carrying certain cell-type specificities and (2) variants independent of cell-type specificities. To study enrichment of CSPs at the risk variants, we can classify the variants into two groups. In group 1, the variants have an unknown probability π~c~ of co-occurring with CSPs Ω~c~ (c = 1, ..., C). In group 2, the variants are nonspecific to the CSPs and thus have probability p~c~ of co-occurring with Ω~c~, where p~c~ is given by the model (4). We assume that each risk variant has probability q of being in group 1 and probability 1 − q of being in group 2. For each complex trait, let A = {A~1~, A~2~} denote the group index of all risk variants. Let {M~j~} denote the CSP index for the jth variant. Let l~1~ = \\|A~1~\\| and l~2~ = \\|A~2~\\| denote the numbers of risk variants in groups 1 and 2, and {z~1c~} and {z~2c~} denote the numbers of risk variants co-occurring with Ω~c~ in each group. We assign a Dirichlet(1,β) prior to q and a Dirichlet($\overset{\rightharpoonup}{a}$) prior to {π~c~}, and we analytically integrate out q and {π~c~} to obtain. P ( A , M \\| X , Ω ) ∝ Γ ( 1 \+ β ) Γ ( l 1 \+ 1 ) Γ ( l 2 \+ β ) Γ ( β ) Γ ( l 1 \+ l 2 \+ 1 \+ β ) Γ ( C ) Γ ( \\| z ⇀ 1 \\| \+ C ) ∏ c = 1 C Γ ( z 1 c \+ 1 ) p c z 2 c ( ∏ j ∈ A ∏ k = 1 K Γ ( \\| α ⇀ \\| ) ∏ s = 1 S Γ ( α s ) ∏ s = 1 S Γ ( n k j s \+ α s ) Γ ( \\| n ⇀ k j \\| \+ \\| α ⇀ \\| ) ) Inference of the model (5) is performed similarly to that of the model (4), where the variables that need to be updated were A and {M~j~}. The hyper-parameter β in the model (5) must be \>1 to favor the null model of no enrichment. Empirically, we have found that β = 10 or the maximum number of disease variants in a linkage disequilibrium (LD) cluster (the set of variants that are in tight LD with a lead variant reported in GWAS; see the next section), whichever is greater, performs well in the sense that no enrichments are found under the null. For each trait, we trained the model (5) on its risk variants and proxy variants. We obtained the list of variants assigned to group 1, which were enriched/depleted with respect to the CSPs and were used to calculate CSP enrichments. The variants assigned to group 2, on the other hand, were independent of the CSPs. Sets of disease risk variants ----------------------------- The disease-associated variants were obtained from the GWAS Catalog. We removed the traits with fewer than five lead variants. We used SNAP (Johnson et al., [@B9]) to identify proxy variants for the lead variants. We used the default setting of SNAP (1000 Genomes Pilot 1 SNPs in the CEU panel within 500 kb of the lead variant) and retained only the proxies with r^2^ \> 0.95 with the lead variant ([Supplementary Data](#SM1){ref-type="supplementary-material"}). We included the proxy variants in our analysis for two reasons: (1) most lead variants reported in GWAS are likely noncausal, since they were selected based on maximum association signals that were confounded by allele frequencies and LD effects, and (2) including proxy variants increased the number of risk variants to be fitted in our predictive model. Calculating Z-scores for epigenetic state enrichment ---------------------------------------------------- At each variant, we have 127 epigenetic states in the 127 epigenomes. Let n~s,g~ denote the number of states s in the gth epigenome cluster as defined in Table [1](#T1){ref-type="table"}, for g = 1, ..., 10, and let n~s,\ −g~ denote the number of state s in the remaining nine clusters. Further, let p~g~ denote the proportion of epigenomes in group g. The z-score for state s in group g at a position is calculated as z = n s g − ( n s g \+ n s , − g ) p g ( n s g \+ n s , − g ) p g ( 1 − p g ) \+ 1 ###### Ten clusters of the 127 Roadmap Epigenomics epigenomes. Group Epigenome mnemonic ----------- --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- 1 BLD.CD14.MONO, BLD.CD14.PC, BLD.CD15.PC, BLD.CD19.PPC, BLD.CD3.PPC, BLD.CD34.CC, BLD.CD4.CD25.CD127M.TREGPC, BLD.CD4.CD25I.CD127.TMEMPC, BLD.CD4.CD25M.CD45RA.NPC, BLD.CD4.CD25M.CD45RO.MPC, BLD.CD4.CD25M.IL17M.PL.TPC, BLD.CD4.CD25M.IL17P.PL.TPC, BLD.CD4.CD25M.TPC, BLD.CD4.MPC, BLD.CD4.NPC, BLD.CD56.PC, BLD.CD8.MPC, BLD.CD8.NPC, BLD.DND41.CNCR, BLD.MOB.CD34.PC.F, BLD.MOB.CD34.PC.M, BLD.PER.MONUC.PC, THYM.FET 2 ESC.4STAR, ESC.H1, ESC.HUES48, ESC.HUES6, ESC.HUES64, ESC.I3, ESDR.CD184.ENDO, ESDR.CD56.ECTO, ESDR.CD56.MESO, IPSC.15b, IPSC.18, IPSC.20B 3 BRN.FET.M, BRN.GRM.MTRX, ESC.H9, ESC.WA7, ESDR.H1.BMP4.MESO, ESDR.H1.NEUR.PROG, IPSC.DF.19.11, IPSC.DF.6.9 4 BLD.CD19.CPC, BLD.CD3.CPC, BLD.CD34.PC, BLD.GM12878, THYM 5 BLD.K562.CNCR, ESDR.H1.BMP4.TROP, ESDR.H1.MSC, GI.CLN.MUC, GI.CLN.SIG, GI.ESO, GI.RECT.SM.MUS, GI.S.INT, GI.STMC.GAST, GI.STMC.MUC, HRT.ATR.R, HRT.FET, HRT.VENT.L, HRT.VNT.R, KID.FET, LNG, LNG.NHLF, MUS.PSOAS, OVRY, PANC, PANC.ISLT, PLCNT.AMN, SKIN.NHDFAD, SKIN.PEN.FRSK.MEL.01, SPLN, VAS.AOR 6 ADRL.GLND.FET, BRN.NHA, BRST.HMEC, BRST.HMEC.35, BRST.MYO, CRVX.HELAS3.CNCR, LNG.A549.ETOH002.CNCR, MUS.HSMM, MUS.HSMMT, SKIN.NHEK, SKIN.PEN.FRSK.KER.02, SKIN.PEN.FRSK.KER.03, SKIN.PEN.FRSK.MEL.03, VAS.HUVEC 7 BONE.OSTEO, FAT.ADIP.DR.MSC, FAT.MSC.DR.ADIP, LNG.IMR90, MUS.SAT, SKIN.PEN.FRSK.FIB.01, SKIN.PEN.FRSK.FIB.02, STRM.CHON.MRW.DR.MSC, STRM.MRW.MSC 8 BRN.ANG.GYR, BRN.ANT.CAUD, BRN.CING.GYR, BRN.DL.PRFRNTL.CRTX, BRN.HIPP.MID, BRN.INF.TMP, BRN.SUB.NIG 9 BRN.CRTX.DR.NRSPHR, BRN.FET.F, BRN.GANGEM.DR.NRSPHR, ESDR.H9.NEUR, ESDR.H9.NEUR.PROG, GI.CLN.SM.MUS, GI.DUO.MUC, GI.RECT.MUC.29, GI.RECT.MUC.31, GI.STMC.MUS, LIV.HEPG2.CNCR, MUS.SKLT.F, MUS.SKLT.M, PLCNT.FET 10 FAT.ADIP.NUC, GI.DUO.SM.MUS, GI.L.INT.FET, GI.S.INT.FET, GI.STMC.FET, LIV.ADLT, LNG.FET, MUS.LEG.FET, MUS.TRNK.FET Predicting GWAS variants ------------------------ In addition to the enrichment analysis, we used CSPs to predict risk variants from GWAS, including both the lead and the proxy variants. As a control, we randomly selected 11,786 dbSNPs from the UCSC browser as the null variants, with minor allele frequencies and dbSNP function predictions matched to those of the risk variants. We used SNAP in the same setting as described above to identify strong proxies for the null variants, and the final set of null variants consisted of 69,087 SNPs ([Supplementary Data](#SM1){ref-type="supplementary-material"}). For each complex trait, we used a generalized linear model (GLM) to predict the risk vs. null variants. We trained the GLMs by using only 50% of the risk variants for each trait and 50% of the null variants. We then calculated the prediction accuracy using the remaining 50% of data. Prediction accuracy was calculated as the area under the curve (AUC) of the precision-recall values for the model. We repeated this procedure 10 times independently and obtained an average AUC for each trait (traits with fewer than five risk variants in either training or testing data were removed from the analysis). We did not use the receiver operating curves (ROCs) to measure power, because the number of risk variants was too small relative to the number of null variants in most traits. For the same reason, we did not use the conventional 10-fold cross-validation method. The predictors in our model were constructed as follows. First, given the epigenetic states {X~·j~} at the jth variant, we calculated the log likelihood from the formula (2) with Ω~c~ for c = 1, ..., C. This yielded C (=48) scores. Second, we calculated the log z-scores for state enrichment in the 10 epigenome clusters, which were transformed to sign(z)^\^ log(\\|z\\|+1). This yielded 25 × 10 = 250 enrichment scores. The enrichment scores were highly correlated. Therefore, we performed principal component analysis (PCA) on the 250 enrichment scores and retained the first 48 principal components (PCs). As a result, at each variant, we had 48 scores for cell-type specificity and 48 for state enrichment, which were used as predictors in our model. The PCA was performed using training data only, and the same PCs were used in the testing data to convert enrichment scores. We further used the epigenetic states in all cell types as predictors in our GLM. Given 25 states per cell type, we had 25 × 127 = 3,175 predictors, using all of which would inevitably over-fit the data, and they were highly correlated. We again used PCA to identify the first 96 PCs as the predictors to be used in the GLMs. We chose 96 PCs so to match with the number of predictors in our first model. As a third model, we used the states in each cell type separately as the categorical predictors to predict GWAS variants. We identified the cell type yielding the best prediction as the single best cell type for predicting GWAS variants. Power analysis -------------- Using 2,473,120 SNPs from Morris et al. ([@B15]), we randomly selected 100 causal SNPs according to the precision-recall curve for each complex trait, i.e., x% of causal variants were selected from the top y% SNPs as ranked by our predictive model, where x* denotes 100^\^ recall and y* was given by (100^\^ x/precision)/2,473,120. We first simulated the test statistics for all variants from N(0, 1) under a null model of no association. We then simulated the effect sizes λ for each causal variant from a normal distribution N(0.1, 0.05), which were then multiplied by −1 or +1 with 50% probability each to reflect protective or deleterious effects. The test statistic corresponding to effect size λ was calculated as $t = \left\lbrack {log{({1 + \lambda})}} \right\rbrack/\sqrt{n}$ under the assumption that each variant can only explain a tiny proportion of the total disease variance, where n* (=2,000) denotes sample size (1,000 cases and 1,000 controls). Due to LD among variants, we further added indirect association to all variants within 500 kb to the causal variant by $rt + \sqrt{1 - r^{2}z}$, where r denotes the correlation between each variant and the causal variant, and z denotes the test statistic of the target variant under null model. This procedure yielded correlated test statistics among variants due to LD. Let {π~i~} be the functional data-predicted probabilities for each variant being causal, and let p~cut~ denote a multiple testing adjusted threshold for significance (e.g., p~cut~ = 0.05). The marginal p-value threshold for each variant is then given by p~i~ = p~cut~π~i~/\\|π\\|. In this way, variants with high probabilities of being causal will receive liberal thresholds, and variants with low probabilities of being causal will receive stringent thresholds. We have previously shown (Zhang and Liu, [@B26]) that this approach can appropriately control the overall false-positive rate in the genome. Finally, power was calculated as the percentage of causal variants located within 1 kb of at least one detected significant variant. Results {#s3} ======= Identification of cell-type-specificity patterns ------------------------------------------------ We used IDEAS (Zhang et al., [@B25]) to jointly infer a 25-state model in the 127 epigenomes from the Roadmap Epigenomics and ENCODE projects. The 25 states captured unique combinations of mean signals of histone marks, which corresponded to the signatures of distinct functional elements as previously verified by experiments. For instance, states with moderate H3K4me3 and high H3K4me1 indicate likely enhancer activities; states with high H3K4me3 and moderate H3K4me1 indicate likely promoter activities; states with high H4K36me3 indicate transcription activities; states with H3K27me3 indicate repressive activities; states with H3K9me3 indicates heterochromatin; and states with low signals in all histone marks indicate no activity. Using the 25-state model predicted across the genome and 127 epigenomes, we can study patterns of cell-type specificity with respect to their putative regulatory functions and use the functions to interpret disease variants. We define a CSP as a partition of the 127 epigenomes such that epigenetic states in epigenomes within the same partition follow the same distribution, while states in epigenomes in different partitions follow different distributions. We developed a Bayesian algorithm to identify 48 major reoccurring CSPs in the genome ([Supplementary Data](#SM1){ref-type="supplementary-material"}), where each CSP represented a unique cell type-specificity pattern (Figure [1](#F1){ref-type="fig"}). One of the 48 CSPs had all epigenomes assigned to one group, which corresponded to non--cell-type-specific regions and occurred in 65.6% of the genome. This CSP constituted mainly low-signal regions or conserved transcription start sites. The remaining 47 CSPs had much lower abundances in the genome, with each occurring in about 0.1--3% of the genome. These 47 CSPs captured cell-type-specific regulatory events and thus are most interesting. ![Genome-wide patterns of cell type specificity. X-axis denotes the 127 epigenomes, with epigenome color keys shown on the top and the right hand side. The cell type abbreviations are given by the Roadmap Epigenomics consortium. Y-axis shows the 48 CSPs. Each row in the matrix denote one epigenome partition pattern, with different groups of epigenomes indicated by black, white and gray. The percentage of the genome carrying each pattern is shown on the right. We also marked 10 clusters of epigenomes that were often together in most patterns.](fgene-08-00071-g0001){#F1} The 47 CSPs revealed roughly 10 distinct groups of epigenomes (Figure [1](#F1){ref-type="fig"}), which agreed well with the known cell-type origins (Table [1](#T1){ref-type="table"}). For instance, most of the lymphocytes (Blood & T-cells and HSC & B-cells) were grouped together (cluster 1) in all CSPs, suggesting that the functional elements in these cell types are positively correlated across the genome. The pluripotent stem cells (ESCs, iPSCs, and ES-deriv) were commonly distributed in two groups (clusters 2 and 3), and the functional elements between the two groups were frequently different. We further obtained a group of ENCODE cell types and epithelial cell types (cluster 6), a group of mesenchymal stem cells and some of their differentiated cell types (cluster 7), a group of brain tissues (cluster 8), and a group of fetal tissues (cluster 10). Of the remaining epigenome groups, cluster 4 contained a small set of primary lymphocytes. Clusters 5 and 9 contained mixed cell types of different origins. Since we did not use the known cell-type origins as input, their agreement with our results confirmed that the inferred CSPs were reasonably accurate. Cell-type-specific enrichment in GWAS variants ---------------------------------------------- We next investigated the enrichment of the 48 CSPs in the disease variants. If the risk variants of a complex trait are enriched in some CSPs, then the corresponding epigenome partitions will inform us of potential functional relationships between the cell types and the trait. For all complex traits in the GWAS Catalog (Welter et al., [@B24]), we treated the lead GWAS variants and their strong proxy variants (LD r^2^ \> 0.95) as the risk variants. We calculated two-sided permutation p-values (10,000 permutations) for the enrichment/depletion of those risk variants in each of the 48 CSPs. As shown in Figure [2](#F2){ref-type="fig"}, the enrichment/depletion of disease variants can be roughly categorized as (1) strongly enriched in all CSPs, (2) moderately enriched in a subset of CSPs, (3) enriched in specific CSPs, or (4) enriched in one or two CSPs and depleted elsewhere. For instance, physical traits (height, BMI, HDL, etc.) tended to be enriched in most CSPs, indicating that they may not be associated with specific cell types. Autoimmune diseases (multiple sclerosis, rheumatoid arthritis, type 1 diabetes, etc.), on the other hand, tended to be enriched in CSPs that uniquely clustered blood and immune cell types. A few mental and nerve-related disorders (Parkinson\'s disease, cognitive performance, bipolar disorder, intelligence, etc.) showed enrichment in a specific set of CSPs that highlighted brain-tissue specificity. In addition, Alzheimer\'s disease showed enrichment in monocytes. ![Enrichment of the 48 cell type specificity patterns in disease variants. The heatmap at top left corner shows the --log10 p-value of enrichment/depletion for the risk variants of all complex trait (y-axis) in each CSP (x-axis). Significant depletion is shown in blue and white (−log10 p-value is multiplied by −1 for depletion), and significant enrichment is shown in red and yellow. The heatmap at lower right corner shows the −log~10~ p-value of enrichment/depletion for the risk variants of 52 traits that have at least 50 lead variants. The upper right panel shows the 48 CSPs.](fgene-08-00071-g0002){#F2} We further evaluated whether specific functional elements are enriched in disease variants. Since most reported GWAS variants are likely tagging the true but unobserved causal mutations, we first used a Bayesian model to sub-select disease variants within each group of variants in strong LD, and we identified those variants showing significant enrichment in CSPs. About three-quarters of the traits in the GWAS Catalog had at least one risk variant enriched in CSPs ([Supplementary Data](#SM1){ref-type="supplementary-material"}). The proportion of enriched variants in each trait ranged from 0 to 76.3%, with a mean of 14.8%. For traits with CSP-enriched risk variants, their risks are likely affected by mutations in a cell-type-specific manner. On the other hand, for traits without CSP-enriched risk variants, their risk variants may not affect cell-type-specific regulation. The number of risk variants available from the GWAS Catalog did not bias our calculation, since the proportion of enriched risk variants in each trait was not associated with the number of risk variants for the trait (Pearson correlation 0.013). We calculated z-scores for each trait using CSP-enriched risk variants to quantitatively measure the enrichment of epigenetic states at the risk variants with respect to the 10 epigenome clusters defined in Table [1](#T1){ref-type="table"}. The z-scores were calculated at each risk variant and then averaged for each trait. We subtracted background z-scores using genome-wide null variants, and the final z-score matrix revealed interesting enrichment of epigenetic states. In particular, the epigenetic states labeling enhancers, transcriptions, and repressions were substantially enriched. As shown in Figure [3](#F3){ref-type="fig"}, for instance, autoimmune and blood-related traits exhibited enhancer (yellow) and transcription (green) enrichment exclusively in the blood cell types (cluster 1). Physical traits, including male baldness, breast size, psoriasis, dental caries, and common traits, had enriched enhancer, transcription, or repression (blue) activities in pluripotent stem cells (cluster 2). Another set of physical traits, including central corneal thickness, longevity, primary tooth development, and intelligence, showed enrichment of enhancer and transcription activity in mesenchymal stem cells (cluster 7). Interestingly, in brain tissues (cluster 8), we observed enriched enhancer activities for Alzheimer\'s disease, response to antipsychotic treatment, schizophrenia, and weight loss. There was barely any enrichment of promoter activities (red) in any epigenome clusters, which was consistent with our observation that promoter activities are highly conserved across cell types. ![Enrichment of epigenetic states in disease variants with respect to the 10 epigenome clusters defined in Table [1](#T1){ref-type="table"}. The left most heatmap shows the mean signal of histone marks in the 25 epigenetic states. State color keys and their putative functions are shown on the left. The right two panels show the enrichment of epigenetic states at the risk variants of each complex trait, with colors reflecting the most enriched states (given by the state color keys) and the strength of enrichments (brighter color means stronger enrichment).](fgene-08-00071-g0003){#F3} Prediction of GWAS variants using cell-type-specificity patterns ---------------------------------------------------------------- Finally, we evaluated how well the epigenetic states and their CSPs can predict GWAS variants. We used the risk variants (without sub-selection) of each complex trait and a set of randomly selected null variants with matched minor allele frequencies and functional annotations as the response variable (binary). We used the log likelihood of the CSPs and the epigenetic state enrichment in the 10 epigenome groups in Table [1](#T1){ref-type="table"} as the predictor variables. For comparison, we also ran two other models to predict GWAS variants. One used the epigenetic states in all epigenomes as predictors, and the other used the epigenetic states in the best-matched single cell type, where the best-matched cell type was identified as the cell type yielding the best prediction. We used the AUC of the precision-recall plot to measure the prediction accuracy of each model for each complex trait. As shown in Figure [4](#F4){ref-type="fig"}, using CSP and state enrichment scores produced substantially better predictions than using the best-matched single cell types, particularly for traits whose risk variants were overall predictable (as reflected by the mean AUC between methods). As expected, the power gain was partially due to the fact that we used more data than single cell types. However, for many traits, our method also outperformed the linear model using all cell types as input. Our result thus confirmed that the combinatorial relationships between functional elements captured by the CSPs could also increase prediction accuracy. ![Power for predicting disease variants. (A) AUC difference of precision-recall curves between our model and single best cell type model (y-axis) plotted with respect to the mean AUC between the two models (x-axis); the mean AUC reflects how well the variants of a complex trait can be predicted overall. (B) is similar to (A), but compares between our model and the model using a linear combination of all cell types.](fgene-08-00071-g0004){#F4} To demonstrate the potential gain in power from using our predictions, we performed a power analysis for detecting association in GWAS on each complex trait, while using our functional data-predicted probability of being causal variants as a prior. As shown in Figure [5](#F5){ref-type="fig"}, our test using the functional priors uniformly boosted the power for detecting causal variants. Without using the priors, the mean power for detecting a causal variant in each trait was 17.2% for our simulation setting. After using the priors, the powers were increased to as much as 51%. As expected, the power gain was positively correlated with the prediction accuracy of our models (p-value 0.00156). It was also trait-dependent, since the traits had different precision recall curves even if their mean AUC-values were similar. ![Power comparison between the conditional test method using functional priors (gray) and the fixed threshold method without priors (black) for detecting causal variants in GWAS. Horizontal line marks the mean power without using priors. Only the top 70 traits whose mean AUCs \>0.05 in our model were shown.](fgene-08-00071-g0005){#F5} Finally, we used 179 credible risk variants for inflammatory bowel disease (IBD) at the SKAP2 gene from Huang et al. ([@B8]) to demonstrate how our functional predictions can prioritize some of the low-probability IBD associations. As shown in Figure [6](#F6){ref-type="fig"}, a single variant within a transcribed region of SKAP2 had the largest probability of association indicated by genetic data alone, while the remaining risk variants had flat but nontrivial probabilities of IBD association as well. This latter observation was due to strong LD within the region. After incorporating our functional predictions, two different variants stood out as being more likely to have an impact on IBD risk, since they were located within T-cell-specific enhancers. In contrast, the originally most significant variant and all other variants had much reduced probabilities of IBD association, including the variants located within the promoter region of SKAP2. This example thus highlights how our approach can borrow information from epigenetic CSPs to pinpoint potential functional variants that are otherwise undistinguishable when using genetic data alone. ![Example of change in IBD association probability before (top) and after (bottom) incorporating functional predictions at SKAP2 gene. Black vertical lines show the probability of IBD association at 179 credible variants obtained by Huang et al. ([@B8]) via fine mapping using genetic data alone. The probabilities are overlaid with IDEAS functional annotation map to highlight how probabilities changed with functions. Overall, green in the functional annotation map indicates transcription, blue indicates repression, red indicates promoter activity, yellow/orange indicates enhancer activity, and gray indicates no regulatory events. The dashed box shows the group (rows) of blood T cells, and the remaining rows in the functional map are blood B & HSC cells.](fgene-08-00071-g0006){#F6} Discussion {#s4} ========== We have introduced a computational approach to identify recurring patterns of cell-type specificity in the genome of 127 human cell types. By focusing on the co-occurrence patterns of epigenetic states, we have been able to use a small number of CSPs to explain most epigenomic variation in the genome. The corresponding epigenome partitions within CSPs agree well with known cell-type origins and are strongly enriched in the risk variants of many complex traits. The enrichment of active and repressive elements suggests both known and novel relationships between cell types and complex traits, and thus offers new insights for interpreting the regulatory effect of DNA mutations on disease risk in a cell-type-specific context. We have further demonstrated that using cell-type specificity could improve prediction of disease variants compared with using a linear model of functional elements alone. The study presented here is complementary to existing work on utilizing functional data in fine mapping. Specifically, our approach is a computationally tractable method for detecting combinatorial patterns of functions across cell types, which can be included as additional predictors in existing methods to improve their power to prioritize disease variants. It should also be possible to use the functional data to perform conditional testing of disease association (Zhang and Liu, [@B26]), where a variant with weaker genetic association could be prioritized over other variants (with stronger genetic association) by using a more liberal threshold, if its functional information was more relevant to the disease. There are a few limitations of the current study. First, we have exclusively focused on predicting disease variants from regulatory marks, which may lead us to miss disease mutations that directly affect protein coding. Our analysis included the H3K36me3 mark in the annotation, and thus the coding variants may be partially predictable by transcription states. It is, however, desirable to include additional and complementary genome annotation to improve prediction. Second, we used log p-values provided by the Roadmap Epigenomics project as input to our segmentation algorithm, by which data bias in different cell types should have been adjusted. The fact that we observed some epigenomic similarity between cell types from different origins, however, warrants more careful investigation. Third, a previous study suggested that 95% of the lead variants reported in the GWAS Catalog might not be causal (Farh et al., [@B4]). This limits our ability to detect epigenomic enrichment in the disease variants. We have alleviated this issue by including proxy variants as well as the lead variants, and we have developed a Bayesian method to sub-select candidate causal variants by explicitly assuming that not all reported variants are causal. However, because only a limited number of disease variants are available in the GWAS Catalog, we have only used logistic linear regression to predict the most likely causal variants. It would be desirable to improve the power further using nonlinear models and machine learning methods if a greater number of variants become available, for example by using whole-genome summary statistics from GWAS or combining the disease variants of closely related traits together via mixed effect models. URLs ---- The list of variants and the software tools used to generate the results in this paper are available in [Supplementary Data](#SM1){ref-type="supplementary-material"}. The IDEAS tool is available through the author\'s website at <http://stat.psu.edu/~yuzhang/IDEAS/>. Summary information on the 127 cell types is available from the Roadmap Epigenomics Consortium at <https://docs.google.com/spreadsheet/ccc?key=0Am6FxqAtrFDwdHU1UC13ZUxKYy1XVEJPUzV6MEtQOXc&usp=sharing#gid=15>. Author contributions {#s5} ==================== YZ conceived, designed, and implemented the study and wrote the manuscript. Conflict of interest statement ------------------------------ The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. YZ is supported by Grant NIH 1R24DK106766. Supplementary material {#s6} ====================== The Supplementary Material for this article can be found online at: <http://journal.frontiersin.org/article/10.3389/fgene.2017.00071/full#supplementary-material> ###### Click here for additional data file. [^1]: Edited by: Douglas Mark Ruden, Wayne State University, United States [^2]: Reviewed by: Jeffrey Mark Craig, Murdoch Childrens Research Institute, Australia; Bernardo Lemos, Harvard University, United States; Jack W. Kent, Texas Biomedical Research Institute, United States [^3]: This article was submitted to Epigenomics and Epigenetics, a section of the journal Frontiers in Genetics	{ "pile_set_name": "PubMed Central" }
Hi my name is Sarah and I will happily eat ALL the chocolate and peanut butter things for the rest of my life. Exhibit A,Exhibit B, Exhibit C….. But first we’re starting with these layered chocolate and peanut butter banana milkshakes. If you follow me on Instagram you may have seen my little mishap a couple of weeks ago when I was trying to take photos of these shakes. My make shift food photography set up consists of a variety of precariously placed items that have been known to fall over every now and then. The last time it happened was Mabel’s fault (my neurotic cat) but this time I blame gravity. Looking on the bright side (because that’s what we do here) my abrupt end to the previous photo shoot meant that I had to revisit this recipe at least one more time. What a happy inconvenience. Coming back to this recipe again I decided it needed more chocolate because what situation doesn’t get better with more chocolate? Feel free to mix in the chocolate sauce to the shake itself or just drizzle a little on top at the end if you don’t want to get too crazy. As far as shakes go, this one is more on the light and airy side while still being deliciously thick. Even better – these shakes are vegan and naturally sweetened with bananas and a little bit of maple syrup. high five I hope you enjoy these milkshakes! Now that the weather is starting to warm up (or so I’ve been told) these are perfect for cooling down and treating yourself without warming up the house. I for one have no problem turning on the oven no matter how hot it is outside, but I know I’m kind of freak for being that way. Layered Chocolate Peanut Butter Banana Milkshakes Layered chocolate and peanut butter banana milkshakes - thick, airy, and oh so decedent. Made with six ingredients! Prep Time10 minutes Total Time10 minutes Ingredients Chocolate Sauce 1 tablespoon coconut oil 2 tablespoons peanut butter 2 tablespoons cocoa powder 1-2 tablespoons maple syrup Shake 2 frozen bananas 1/4 cup peanut butter 1 can lite coconut milk, chilled in the fridge first Instructions Sauce To make the chocolate sauce melt the coconut oil and peanut butter in a small sauce pan. Once melted remove them from the heat and stir in the cocoa powder and maple syrup until fully incorporated. Set aside to cool while blending the milkshake Milkshake Cut the frozen banana into chunks for easier blending. Scoop the fat out of the top of the coconut milk and add it to a blender along with the frozen banana chunks and peanut butter. Blend until thick and smooth. If you want to thin out the milk shake add a little bit of the coconut water from the can to the blender.	{ "pile_set_name": "Pile-CC" }
The Limey The Limey #3: Internet Troubles Which UK Internet Service Provider is going to look out for my gaming needs? I'm stealing my dear old dad's bandwidth as I type. Three weeks or so after I got back to England, I'm working during the weekdays flip-flopping between my parent's house and my brother's house. Both establishments have ADSL broadband, while the house I'm about to move into has none. Yet. I'm sitting here watching a 640MB patch for the European version of World of Warcraft stream fairly quickly to my desktop. But I'm starting to get a little concerned. My dad's Internet plan has a monthly data cap on it. So does my brother's. Both members of my family get to use a maximum of 40GB per month; once it's used up, they can pay an extra four pounds (about $6 given the current exchange rate) and step the plan up to 80GB per month. But they personally never, ever, ever come close to this data cap. Myself, however, well that's a different story. Did I forget to mention that I left my laptop here overnight downloading the whole WoW client? Yeah, that thing clocks in at like 4.5GB. I've already consumed more than 10 percent of the monthly allowance with just two downloads. This troubles me greatly. Un'Goro Crater: Downloading this zone costs bandwidth. For starters, my work for GameSpy can be bandwidth-intensive; managing media files, uploading, downloading, streaming, etc. But it's my life as an online gamer or indeed, a person that relies on the Internet for daily news, information and entertainment that's going to thump through that 40GB per month limit very quickly. So what are my options? The key to solving the riddle was to take some time out and do a little research into the various ISPs that the UK has to offer. Not all of the providers are as draconian with bandwidth it would seem, but one small factor I forgot to mention pertaining to my family's ISP is that broadband is free; it comes as no extra charge with the telephone landline, and both locations regularly experience download rates ranging from 4-6 Mbps. That's a really nice incentive to the more casual users or those who don't use BitTorrent. As an aside, I've just started downloading patch #3 for WoW. This one only comes in at 45MB.	{ "pile_set_name": "Pile-CC" }
require 'spec_helper' require 'pact/consumer/configuration' module Pact::Consumer::Configuration describe MockService do let(:world) { Pact::Consumer::World.new } let(:port_number) { 1234 } before do Pact.clear_configuration allow(Pact::MockService::AppManager.instance).to receive(:register_mock_service_for).and_return(port_number) allow(Pact).to receive(:consumer_world).and_return(world) end describe "configure_consumer_contract_builder" do let(:consumer_name) {'consumer'} subject { MockService.build :mock_service, consumer_name, provider_name do port port_number standalone true verify true end } let(:provider_name) { 'Mock Provider' } let(:consumer_contract_builder) { instance_double('Pact::Consumer::ConsumerContractBuilder') } let(:url) { "http://localhost:#{port_number}" } it "adds a verification to the Pact configuration" do allow(Pact::Consumer::ConsumerContractBuilder).to receive(:new).and_return(consumer_contract_builder) subject expect(consumer_contract_builder).to receive(:verify) Pact.configuration.provider_verifications.first.call end context "when standalone" do it "does not register the app with the AppManager" do expect(Pact::MockService::AppManager.instance).to_not receive(:register_mock_service_for) subject end end context "when not standalone" do subject { MockService.build :mock_service, consumer_name, provider_name do port port_number standalone false verify true pact_specification_version '1' end } it "registers the app with the AppManager" do expect(Pact::MockService::AppManager.instance).to receive(:register_mock_service_for). with(provider_name, url, pact_specification_version: '1', find_available_port: false). and_return(port_number) subject end end context "without port specification" do let(:url) { 'http://localhost' } subject { MockService.build(:mock_service, consumer_name, provider_name) {} } it "registers the app with the AppManager with find_available_port option" do expect(Pact::MockService::AppManager.instance).to receive(:register_mock_service_for). with(provider_name, url, pact_specification_version: '2', find_available_port: true). and_return(port_number) subject end end context "without port specification and old pact-mock_service" do let(:url) { 'http://localhost' } subject { MockService.build(:mock_service, consumer_name, provider_name) {} } it "checks and raises an error" do expect(Pact::MockService::AppManager.instance).to receive(:register_mock_service_for). with(provider_name, url, pact_specification_version: '2', find_available_port: true). and_return(nil) expect { subject }.to raise_error(/pact-mock_service.+does not support/) end end end end end	{ "pile_set_name": "Github" }
Q: Normalizing raw text in different formats to create objects in Ruby I have three text files with the exact same type of information but with different delimiters. One is a CSV, one uses spaces as delimiters, and the last one uses \| (pipe) as the delimiter. The delimiters are different, but each row in all of the files has exactly the same format. So in the pipe-delimited file, the format is FirstName \| LastName \| DOB \| City \| State \| ZIP (there is a space before and after each pipe). The other two files use the exact same order but with the other delimiters. All rows are unique. The files do not have headers. I want to go through all of these files and create an instance of my Person object for each row. The class looks like this: class Person attr_reader :first_name, :last_name, :d_o_b, :city, :state, :zip def initialize(first_name, last_name, ...) @first_name = first_name @last_name = last_name ... end ... etc. end I want to parse this data and create the objects in the cleanest and most readable way -- performance/scaling/etc. are unimportant here. What approach would be best for doing this? My initial idea is to convert all of the files to CSV somehow (perhaps with a gsub), then make a nested array from this data, and then iterate over the array to create the objects, but I am looking for any possible better/cleaner ideas. A: Something along these lines should work. You'll have to be careful if your city names have commas or spaces. files = ['file1.txt', 'file2.txt'] people = [] files.each do \|f\| File.open(f).each do \|line\| # Split line along any of the delimeters args = line.strip.split(/[ ,\\|]+/) # The * (splat) unpacks the array into an argument list people << Person.new(*args) end end	{ "pile_set_name": "StackExchange" }
Cyclists use stationary bicycle trainers for training due to inclement weather, time constraints, and convenience and to achieve specific athletic objectives, such as performing controlled drills to improve their cycling performance. Most commonly cyclists attach their own bicycle to a portable trainer; however, occasionally they may use a stationary bicycle. Most existing bicycle trainers consist of an apparatus that attaches to the rear wheel of the cyclist's bicycle in order to apply resistance which can vary throughout the workout. Additionally, most often, the front wheel sits in a simple rest, or the front wheel is removed and the front fork of the bicycle is mounted to a component of the trainer in order to support the front of the bicycle, which remains stationary during the workout. Stationary bicycles use the same method of applying resistance to the rear wheel to vary the difficulty of the workout. Many indoor bicycle manufacturers provide compatible software programs that incorporate “virtual reality” effects where the user views a rider on a screen in front of him and the resistance applied to the bicycle on the trainer increases as the rider on the screen approaches a hill. Some of the programs also incorporate a steering option for the rider to simulate cornering while viewing the rider on the screen cornering right or left. These virtual reality programs use an increase in resistance applied to the rear wheel to simulate the increasing workload of an uphill effort and a decrease in resistance to simulate the decreasing workload of downhill effort. U.S. Pat. No. 5,279,529 (the '529 patent) uses existing torque or resistance generators (load generators) to increase and decrease workload resistances in simulating incline and decline riding. It describes a pedal platform apparatus that simulates uphill or downhill riding, and focuses on assisting with cycling while in the standing cycling position. The '529 patent also provides for changing pedal positioning. U.S. Pat. No. 4,976,424 (the '424 patent) allows for adjustable incline and decline of the front wheel achieved by manually positioning the fork mount for the purpose of creating a ‘slight uphill’ position for the comfort of the cyclist. The '424 patent simulates uphill and downhill resistance by adjusting the force applied via a resistance generator. To maintain constant resistance, the front fork support described in U.S. Pat. No. 4,976,424 moves in response to the cyclist's shifting weight to keep the back wheel in contact with the resistance rollers. U.S. Patent Publication. No. 2002/20107114 (the '114 publication) allows for automatic inclination and declination of the front of the trainer to simulate uphill and downhill riding. To achieve inclination and declination of the front of the trainer the '114 publication describes utilizes a telescoping frame of a stationary bike which in turn raises and lowers the pedal height position. U.S. Pat. No. 7,303,510 (“the '510 patent) allows for automatic inclination and declination of the front wheel of a bicycle using an elevator assembly and a wheel support assembly that is operatively coupled to the elevator assembly. To achieve proper declination of the front wheel to simulate downhill orientation, the '510 patent requires the use of elevation legs to support the bicycle some distance above the ground when in level orientation. In addition, the '510 patent provides for the wheel support assembly to be modified to attach to the bicycle's front fork through the use of a fixedly attached cylinder approximating a wheel axle. By fixedly attaching the bicycle's front fork to the wheel support assembly the horizontal movement of the fork in relation to the elevator assembly is removed. Without this horizontal movement, the ability to raise or lower the front fork of the bicycle is negated. While these references provide some features to enhance bicycle trainers, there is still room for improvement in bicycle training devices. For example, none of these approaches allow for the simulation of hill training addressing resistance, incline, decline, and body positioning. In addition, none of these approaches allows for the simulation of decline hill training and body positioning without the need for additional components to raise the bicycle off the ground.	{ "pile_set_name": "USPTO Backgrounds" }
Dilution of human mesenchymal stem cells with dermal fibroblasts and the effects on in vitro and in vivo osteochondrogenesis. The stromal elements of human bone marrow include cells, referred to as mesenchymal stem cells (MSCs), that have the potential to differentiate into bone, cartilage, fat, and hematopoietic-supportive stromal tissue. MSCs have been isolated and maintained in culture, and in vivo and in vitro assays have been used to show that these cultured cells possess osteochondral potential. Human mesenchymal stem cells (hMSCs) were combined in a range of proportions with human dermal fibroblasts (hDFs), shown to be devoid of osteochondral potential, and tested in these assays. Results suggest that hMSCs may be intentionally "contaminated" with 25-50% hDFs and still elicit a positive response in alkaline phosphatase and calcium in vitro osteogenic assays, form cartilage in pellet culture conditions, and produce bone when loaded into porous hydroxyapatite-tricalcium phosphate ceramic cubes and then implanted subcutaneously into immunocompromised mice. Although hMSCs can be purified and culture-expanded as a homogeneous subset of marrow cells, the dilution results reported here are encouraging for the prospective use of these cells in clinical applications, where repair grafts that contain 100% hMSCs almost surely will become infiltrated with host connective tissue and vasculature, which will dilute the initial concentration of hMSCs.	{ "pile_set_name": "PubMed Abstracts" }
1. Field of the Invention The present invention relates to compression algorithms for discrete values having audio and/or image information, and particularly to transformation algorithms, which are particularly to be used in encoders that are transformation-based, which means perform quantization/coding not of the original audio and/or image signals but comprise transformation into a spectral range prior to quantization/coding. 2. Description of the Related Art Modern audio encoding methods, such as MPEG Layer3 (MP3) or MPEG AAC use transformations, such as the so-called modified discrete cosine transformation (MDCT) to obtain a block-wise frequency representation of an audio signal. Normally, such an audio encoder receives a stream of time-discrete audio samples. The stream of audio samples is windowed to obtain a windowed block of, for example, 1024 or 2048 windowed audio samples. For windowing, different window functions are used, such as a sine window, etc. The windowed time-discrete audio samples are then converted into a spectral representation via a filter bank. In principle, a Fourier transformation, or for specific reasons a variation of the Fourier transformation, such as FFT or, as explained above, MDCT, can be used. The block of audio spectral values at the output of the filter bank can then be further processed, if required. In the above-mentioned audio encoders, quantization of the audio spectral values follows, the quantization levels being typically chosen such that the quantization noise introduced by quantization lies below the psycho-acoustic masking threshold, i.e. is “masked away”. The quantization is a lossy encoding. To obtain a further data amount reduction, the quantized spectral values are then entropy encoded, for example via Huffman encoding. By adding side information, such as scale factors, etc., a bit stream multiplexer forms a bit stream from the entropy encoded quantized spectral values, which can be stored or transmitted. In the audio decoder, the bit stream is divided into encoded quantized spectral values and side information via a bit stream demultiplexer. The entropy encoded quantized spectral values are first entropy decoded to obtain the quantized spectral values. The quantized spectral values are then inversely quantized to obtain decoded spectral values, which have quantization noise, which lies below the psycho-acoustic masking threshold and will thus be inaudible. These spectral values will then be converted into a time representation via a synthesis filter bank to obtain time-discrete decoded audio samples. A transformation algorithm inverse to the transformation algorithm has to be used in the synthesis filter bank. Additionally, windowing has to be cancelled after the frequency time inverse transformation. To obtain a good frequency selectivity, modern audio encoders typically use block overlapping. One such case is illustrated in FIG. 12a. First, for example, 2048 time-discrete audio samples are taken and windowed via a means 402. The window representing means 402 has a window length of 2N samples and provides a block of 2N windowed samples on the output side. In order to achieve window overlapping, a second block of 2N samples is formed via a means 404 which is illustrated in FIG. 12a, merely for clarity reasons, separately from the means 402. The 2048 samples fed into means 404 are, however, not the time-discrete audio samples immediately adjacent to the first window, but comprise the second half of the samples windowed by means 402 and comprise additionally merely 1024 “new” samples. The overlapping is symbolically illustrated by means 406 in FIG. 12a, which effects a degree of overlapping of 50%. Both the 2 N windowed samples output by means 402 and the 2N windowed samples output by means 404 are then subject to the MDCT algorithm via means 408 and 410, respectively. According to the known MDCT algorithm, means 408 provides N spectral values for the first window, while means 410 also provides N spectral values, but for the second window, wherein an overlapping of 50% exists between the first window and the second window. As illustrated in FIG. 12b, in the decoder, the N spectral values of the first window are supplied to means 412, which performs an inverse modified discrete cosine transformation. The same applies for the N spectral values of the second window. These are supplied to means 414, which also performs an inverse modified discrete cosine transformation. Both means 412 and means 414 each provide 2N samples for the first window and 2N samples for the second window, respectively. In means 416, which is designated by TDAC (TDAC=time domain aliasing cancellation) in FIG. 12b, the fact that the two windows are overlapping is considered. Particularly, a sample y1 of the second half of the first window, which means with an index N+k, is summed with a sample y2 of the first half of the second window, which means with an index k, so that N decoded time samples result on the output side, which means in the decoder. It should be noted that by the function of means 416, which is also referred to as an add function, the windowing performed in the encoder illustrated schematically in FIG. 12a is considered automatically, so that no explicit “inverse windowing” has to be performed in the decoder illustrated in FIG. 12b. When the window function implemented by means 402 or 404 is referred to as w(k), wherein the index k represents the time index, the condition has to be fulfilled that the window weight w(k) squared added to the window weight w(N+k) squared together results in 1, wherein k runs from 0 to N−1. If a sine window is used, the window weightings of which follow the first half wave of the sine function, this condition is always fulfilled, since the square of the sine and the square of the cosine for every angle together result in the value of 1. It is a disadvantage of the windowing method with subsequent MDCT function described in FIG. 12a that windowing is achieved by multiplication of a time-discrete sample value, when considering a sine window, with a floating-point, since the sine of an angle between 0 and 180 degrees does not result in an integer, except the angle of 90 degrees. Even when integer time-discrete samples are windowed, floating-point numbers result after windowing. Thus, even when no psycho-acoustic encoder is used, which means when a lossless encoding is to be obtained, quantization is required at the output of means 408 and 410, respectively, in order to be able to perform a reasonably manageable entropy encoding. Generally, currently known integer transformations for lossless audio and/or video encoding are obtained by separating the transformations used there into Givens rotations and by applying the lifting scheme to every Givens rotation. Thereby, a rounding error is introduced in every step. For subsequent stages of Givens rotations, the rounding error keeps accumulating. The resulting approximation error becomes particularly problematic for lossless audio encoder approaches, particularly when long transformations are used, which provide, for example, 1,024 spectral values, such as it is, for example, the case in the known MDCT with overlap and add (MDCT=modified discrete cosine transformation). Particularly in the higher frequency range, where the audio signal typically has a very low amount of energy anyway, the approximation error can quickly become larger than the actual signal, so that this approach is problematic with regard to lossless encoding and particularly with regard to the encoding efficiency obtainable thereby. With regard to audio encoding, integer transformations, which means transformation algorithms generating integer output values, are particularly based on the known DCT-IV, which considers no constant component, while integer transformations for image applications are rather based on the DCT-II, which particularly contains the provisions for the constant component. Such integer transformations are described, for example, in Y. Zeng, G. Bi and Z. Lin, “Integer sinusoidal transforms based on lifting factorization”, in Proc. ICASSP'01, May 2001, pp. 1,181-1,184, K. Komatsu and K. Sezaki, “Reversible Discrete Cosine Transform”, in Proc. ICASSP, 1998, Vol. 3, pp. 1,769-1,772, P. Hao and Q. Shi, “Matrix factorizations for reversible integer mapping”, IEEE Trans. Signal Processing, Signal Processing, Vol. 49, pp. 2,314-2,324, and J. Wang, J. Sun and S. Yu, “1-d and 2-d transforms from integers to integers”, in Proc. ICASSP'03, Hong Kong, April 2003. As has been explained above, the integer transformations described there are based on the separation of the transformation into Givens rotations and on the application of the known lifting scheme to the Givens rotations, which involves the problem of accumulating rounding errors. This is particularly due to the fact that rounding has to be performed several times within one transformation, which means after every lifting step, so that particularly in long transformations, which involve correspondingly many lifting steps, rounding has to be performed particularly often. As has been explained, this results in an accumulated error and particularly in a relatively expensive processing, since rounding is performed after every lifting step to perform the next lifting step.	{ "pile_set_name": "USPTO Backgrounds" }
NoJPEG - danmaz74 http://nojpeg.org/ ====== atoponce Please don't put into a presentation what can be put into a single HTML page. ------ lcedp Why not .svg instead of .eps? ~~~ danmaz74 Personally, I would agree with you.	{ "pile_set_name": "HackerNews" }
SALT LAKE CITY — A Utah Jazz mobile app "system error" got a lot of fans' hopes up that they'd won free tickets to tonight's big game against the defending NBA champions. Tipoff is approaching and some people are still left in the dark, not knowing whether or not they did or didn't win seats for the Jazz's nationally televised contest against the Dallas Mavericks (8:30 p.m. MT tipoff). This afternoon, those with the Jazz app on their smart phones received a message informing them, "Congratulations! You are a winner of two tickets for tonight's Jazz vs. Mavericks game. Click the "VIEW" button for details." Problem was, no details were available. A while later, the official Twitter account of the Utah Jazz (@utahjazz) announced the following: "We experienced a system error, and you may have received a message indicating you have won tickets. We will have details momentarily." Some fans have received ticket notification through emails — as the Jazz explained they'd do through a tweet — and the Jazz's Flash Seats system. Others, however, continue to wait for official word on whether they indeed won tickets for tonight or not. "Seeing others win their @utahjazz tix while others are left hanging," Nick Newman wrote on Twitter. "Hope Jazz can make up for this by following through and giving me tix." "This is ridiculous to get our hopes up and then completely leaving (sic) us hanging like this," Twitter user @ChaseAmes wrote. "I have clicked the notification multiple times. It worked once...for about 10 seconds. Then stopped," @bshums tweeted. Added @DanielTate: "No apology to us losers yet." The Deseret News is still waiting for an official explanation from the Jazz. It's unknown how many app users received the original winning ticket notification, and how many actually won tickets. The Jazz website says 500 tickets will be up for grabs for the upcoming Jimmer game, when the Kings visit Utah on Jan. 28.	{ "pile_set_name": "Pile-CC" }
Identification of hepatotoxic and nephrotoxic potential markers of triptolide in mice with delayed-type hypersensitivity. Triptolide (TP) is the crucial active ingredient of Tripterygium glycoside tablets and has been shown to have a significant therapeutic effect on delayed-type hypersensitivity (DTH)-related diseases. However, due to its potential hepatotoxicity and nephrotoxicity, adverse reactions have often been observed in long-term treatment regimens. Therefore, it is meaningful to find metabolic markers for toxicity for early diagnosis. In this study, a feasible strategy using HPLC-HRMS method combined with multivariate statistical analysis to discover toxic potential markers of TP was developed. TP was used to treat a DTH mouse model at a therapeutic dose (45μg/kg) and toxic dose (900 μg/kg). The metabolic profiles of the liver, kidney and plasma were characterized by HPLC-Q/TOF MS. Significant differences in the metabolite profiles of the liver, kidney and plasma existed between the toxic and therapeutically dosed mice. Forty-six metabolites were identified and 27 of them may be related to toxicity based on a structure-toxicity prediction model. Using OPLS-DA analysis, the metabolite profiles between the two dose groups could be well distinguished. It was found that 18, 4 and 4 metabolic markers were altered in the liver, kidney and plasma, respectively; 15, 4 and 3 of these metabolic markers were predicted to be toxic. Two toxic markers detected both in mouse plasma and human liver microsomes following incubation with TP showed great potential as early diagnosis markers for TP hepatotoxicity and nephrotoxicity.	{ "pile_set_name": "PubMed Abstracts" }
Introduction {#s1} ============ Children and adolescents who were born before 33 weeks\' gestation (very preterm; VPT) show poorer performance compared to controls on a variety of memory tasks, including working, spatial and episodic memory in childhood and adolescence [@pone.0034858-Woodward1]--[@pone.0034858-Anderson1]. Damage to the hippocampus, possibly due to hypoxia-ischemia, has been postulated to underlie memory deficits in VPT populations [@pone.0034858-Isaacs1], [@pone.0034858-Gimenez1], [@pone.0034858-Isaacs2]. However, only a few studies to date have explored the functional neuroanatomy of mnemonic processing in VPT individuals. Curtis and colleagues [@pone.0034858-Curtis1] reported alterations in VPT children compared to controls in the caudate nucleus during completion of a spatial working memory task, while Gimenez and colleagues [@pone.0034858-Gimenez2] described increased activation in right hippocampus during the encoding of novel face-name pairs in VPT adolescents. Our group previously demonstrated altered fronto-temporal activation in VPT young adults during performance of a verbal paired associates learning task, and fronto-parieto-occipital alterations during performance of a visual version of this task [@pone.0034858-Lawrence1], [@pone.0034858-Narberhaus1]. These studies investigated heterogeneous groups of VPT individuals [@pone.0034858-Curtis1], [@pone.0034858-Gimenez2], or excluded individuals with severe brain injury [@pone.0034858-Lawrence1], [@pone.0034858-Narberhaus1]. Since VPT birth may be accompanied by different types of adverse neonatal events and associated brain damage, it would be important to study early events in relation to adult neuroanatomical changes. The most common form of brain injury following VPT birth is periventricular haemorrhage (PVH), which is well-recognized on neonatal cranial ultrasounds [@pone.0034858-Stewart1]. PVH may occur either in isolation (i.e. Uncomplicated PVH -- UPVH), when confided to the germinal matrix, or may be concomitant with ventricular dilatation (VD; PVH+VD), following extension of the haemorrhage in the lateral ventricles [@pone.0034858-Paneth1]. The greatest degree of neonatal insult, i.e. PVH+VD, is likely to cause the greatest disruptions in brain growth in VPT individuals [@pone.0034858-Gressens1], [@pone.0034858-Levitan1]. VPT children with PVH+VD were found to have reduced subcortical grey matter compared to their VPT peers without PVH+VD [@pone.0034858-Kesler1]. In adolescence, VPT individuals with PVH+VD exhibited more numerous cortical and subcortical structural alterations compared to VPT individuals with UPVH and those with normal ultrasound results, with differences being noted in frontal and temporal cortices, thalamus, corpus callosum and cerebellum [@pone.0034858-Nosarti1]. Impaired cortical development following UPVH in VPT infants has also been described [@pone.0034858-Vasileiadis1]. In addition, individuals who experienced PVH+VD are the most vulnerable to developmental compromise [@pone.0034858-Vollmer1]. For instance, PVH+VD was associated with increased risk of deficits in visual associative learning in school-aged VPT children [@pone.0034858-Fletcher1], and with lower IQ and increased behavioural problems in VPT adolescents [@pone.0034858-Nosarti2]. The impact of UPVH on the neurodevelopment of VPT individuals has been a matter of debate [@pone.0034858-Inder1], however, there is evidence that even UPVH may exert some deleterious effect on specific aspects of neurodevelopment, such as memory and language functions [@pone.0034858-Ross1]--[@pone.0034858-Downie1]. To our knowledge, no study to date has investigated whether the functional neuroanatomy of memory processing in VPT individuals varies according to their degree of neonatal brain injury. Verbal paired associates learning tasks are used to assess the episodic memory processes [@pone.0034858-Rushe1]--[@pone.0034858-Meltzer1], which are implicated in the formation of new memory traces (encoding processes), in the maintenance of these memory traces over time (storage processes), and in supporting access to stored memory traces at a later time (retrieval processes), the means of which are recognition and recall [@pone.0034858-Tulving1]. In comparison to storage processes, which are temporarily distributed, encoding and retrieval processes happen at specific time points and are therefore well suited to be studied with fMRI [@pone.0034858-Buckner1]. We used fMRI with a verbal paired associates learning task we previously used [@pone.0034858-Lawrence1], [@pone.0034858-Bhattacharyya1] in four groups of participants with different degrees of severity of neonatal brain injury or no brain injury: (1) VPT young adults with a history of PVH+VD; (2) VPT young adults with a history of UPVH; (3) VPT young adults with no history of neonatal brain injury; (4) term-born controls. In the current study, encoding of paired associates was studied for pairs of words and retrieval was assessed by the production of words to specific cues (cued-recall) [@pone.0034858-Cabeza1]. As both verbal encoding and recall processes are mediated by fronto-temporo-parietal cortices [@pone.0034858-Meltzer1], [@pone.0034858-Cansino1]--[@pone.0034858-Fletcher3], we hypothesized that there would be differential activation of this network in VPT individuals with differing degrees of neonatal brain injury [@pone.0034858-Nosarti1]. We predicted that greater functional neuroanatomical alterations would be associated with increasing severity of neonatal brain injury. We further analyzed structural MRI data to investigate the association between functional neuroanatomical alterations and potential differences in brain structure [@pone.0034858-Lawrence1]. Methods {#s2} ======= Ethics Statement {#s2a} ---------------- Ethical approval for the study was granted by King\'s College Hospital Research Ethics Committee. All participants gave their written informed consent to undergo assessments. Participants {#s2b} ------------ Between 1979 and 1984, 368 infants born very preterm (\<33 gestational weeks) were admitted to the neonatal unit at the University College London Hospital (UCHL), and survived to be discharged. All VPT individuals received neonatal ultrasound scans daily for the first 4 days, at 1 week, and weekly until discharge from the hospital [@pone.0034858-Stewart1]. A linear-array ultrasound scanner (ADR 2130) equipped with a 5 or 7 MHz probe was used to perform the scans. The images were either stored on videotapes or as Polaroid photographs. These infants were all enrolled for participation in longitudinal follow-up studies [@pone.0034858-Costello1]--[@pone.0034858-Roth1]. At 14--15 years, 269 individuals of the original cohort agreed to be assessed. Results of the adolescent assessment have been previously published [@pone.0034858-Nosarti1], [@pone.0034858-Nosarti3], [@pone.0034858-Stewart3]. At age 20 years, 94 individuals of those assessed in adolescence underwent further neuropsychological assessment [@pone.0034858-Allin1]. A sub-sample of these individuals participated in a series of fMRI studies [@pone.0034858-Lawrence1], [@pone.0034858-Narberhaus1], [@pone.0034858-Nosarti4], [@pone.0034858-Lawrence2]. The current study included 19 of those VPT individuals who had previously participated in fMRI studies and 22 newly--recruited VPT individuals. VPT study participants were chosen on the basis of their neonatal ultrasonographic findings. These were classified according to previously specified criteria [@pone.0034858-Nosarti1]: normal neonatal ultrasonographic findings; UPVH: PVH into the germinal layer or ventricles without subsequent ventricular dilatation or parenchymal involvement; PVH and VD: PVH with dilatation of either one or both lateral ventricles. However, the degree of ventricular dilatation was inadequate to meet the diagnostic criteria for hydrocephalus. All VPT participants were dextral, as assessed by clinical neurological examination at 14--15 years of age. Exclusion criteria were: severe head injury, stroke, epilepsy and multiple sclerosis, severe eyesight impairment, hearing and/or motor impairment, metal implants or a fitted pacemaker, operations to the head or the spine, claustrophobia, and pregnancy for female participants. Term-born control data were drawn from healthy individuals previously studied and were selected according to age, handedness and gender in order to be comparable to the VPT participants [@pone.0034858-Lawrence1], [@pone.0034858-Narberhaus1], [@pone.0034858-Nosarti4], [@pone.0034858-Lawrence2]. Exclusion criteria, other than those common to the VPT study participants, were: birth complications (e.g., preterm birth \<37 weeks of gestation, low birth weight defined as \<2500 grams, endotracheal mechanical ventilation), prolonged gestation (greater than 42 weeks), and history of psychiatric illness. All participants were English native speakers. Sample Characteristics {#s2c} ---------------------- One VPT participant with a history of psychiatric illness was excluded from the analyses. Twelve VPT young adults with a history of PVH+VD (newly recruited), 17 with a history of UPVH (9 previously studied and 8 newly recruited), 12 VPT young adults with normal ultrasonographic findings (10 previously studied and 2 newly recruited), and 17 term-born controls were studied (all previously studied). Information about sex, age at assessment, educational level and socio-economic status (SES), categorized according to a standard occupational classification [@pone.0034858-HMSO1], was available for all study participants. The four groups did not differ significantly in sex \[x^2^ ~(3)~ = 0.45, p\>0.05\], SES \[x^2^ ~(6)~ = 5.14, p\>0.05\] and educational level \[x^2^ ~(9)~ = 12.48, p\>0.05\], but there were significant between-group differences in age at assessment \[F ~(3,\ 54)~ = 9.88, p\<0.001\]. Post-hoc comparisons showed that the PVH+VD group was significantly older than the normal VPT \[Mean difference = 3.87, p\<0.01\] and the control groups \[Mean difference = 3.83, p\<0.01\]. Neonatal data i.e. birth-weight (grams) and gestation at birth (weeks) were previously collected for VPT study participants only. There were no significant differences in birth-weight \[F ~(2,\ 38)~ = 1.42, p\>0.05\] and gestation at birth \[F ~(2,\ 38)~ = 0.66, p\>0.05\] between the three VPT groups. [Table 1](#pone-0034858-t001){ref-type="table"} displays descriptive statistics for the neonatal and socio-demographic data. 10.1371/journal.pone.0034858.t001 ###### Neonatal and socio-demographic data of the study groups. ![](pone.0034858.t001){#pone-0034858-t001-1} Variable[+](#nt101){ref-type="table-fn"} PVH+VD (n = 12) UPVH (n = 17) Normal VPT (n = 12) Controls (n = 17) ---------------------------------------------------- ------------------ ------------------ --------------------- --------------------------------------- Neonatal/socio-demographic characteristics Birth-weight (g) 1122.33 (395.60) 1274.47 (396.70) 1388.92 (372.58) n/a [++](#nt102){ref-type="table-fn"} Gestation at birth (weeks) 28.42 (2.64) 28.76 (2.14) 29.5 (2.43) n/a Males/Females (number) 7/5 8/9 6/6 8/9 Age (yrs) at assessment \* 24.58 (2.48) 22.65 (2.57) 20.69 (1.92) 20.75 (1.37) Socio-economic status at assessment (number) ^a^ I -- II 6 10 6 7 III 6 5 5 5 IV -- V 0 2 1 4 Educational level [b](#nt103){ref-type="table-fn"} O-level only 3 2 0 1 A-level or exultant 2 6 7 5 3^rd^ level education 7 9 5 9 Mean and standard deviation (SD) are presented, unless otherwise stated. n/a = non-applicable \p\<0.001, ^a^ For controls n = 1 missing data. For controls n = 2 missing data. Neuropsychological data {#s2d} ----------------------- Four subtests from the Wechsler Abbreviated Scale of Intelligence (WASI) [@pone.0034858-Wechsler1] (i.e. vocabulary, block design, similarities and matrix reasoning), were used to estimate verbal, performance and full-scale IQ. fMRI Task {#s2e} --------- To examine the neural correlates of paired-associate learning, we used a verbal task based on the Paired Associates Learning subtest of the Wechsler Logical Memory Scale -- Revised [@pone.0034858-Wechsler2]. This task was used by our group in previous studies [@pone.0034858-Lawrence1], [@pone.0034858-Bhattacharyya1]. The task involved an encoding, a recall and a 'fonts' discrimination condition (baseline), as well as a 'blanks' low-level baseline, presented in that order, in a total of 16 blocks of 8 pairs of word-stimuli (four blocks with a total of 32 presentations of word-pairs per condition). All the words used for the task were selected from the MRC Psycholinguistics Database [@pone.0034858-Wilson1] and were matched in number of letters, frequency in the written language and meaningfulness [@pone.0034858-Kucera1]. Each block of word-pairs lasted 40 seconds (s). The inter-stimulus interval i.e. the time between the display onsets of two pairs of stimuli was 5 s and was given by the sum of the duration of the silent period (3.5 s) and the compressed image acquisition (1.5 s). The long inter-stimulus interval was chosen to allow for the longer reaction time latencies of very preterm-born individuals and to provide them with a slightly longer than usual interval of rest between trials [@pone.0034858-Rose1]. The experimental conditions and the baseline were presented 4 times each and are described below ([Figure 1](#pone-0034858-g001){ref-type="fig"}): [Encoding condition]{.ul} -- Participants were visually presented with pairs of nouns written on blue rectangles, and were instructed to verbally say ('Yes'/'No') if they thought the nouns of each pair were associated. The order of the presentation of the word-pairs was randomized across blocks. [Recall condition]{.ul} -- A single word from each pair previously presented during encoding, was displayed with a question mark and participants were required to verbally say the other word of the pair it had been presented with. On failure to recall the word, participants were instructed to articulate the word 'pass'. ['Fonts' discrimination condition]{.ul} -- It required the participants to overtly say ('Yes'/'No') when asked if the fonts of the words of each pair were the same. This condition was designed to control for activation associated to the processing of non-mnemonic information (i.e. reading and semantic processing). An 'instruction question' was displayed on the computer screen, prior to the presentation of each encoding ('Do these words seem to go well together?'), recall ('Which word was associated with this?') and 'fonts' discrimination condition ('Are the fonts of these two words the same?'). ['Blanks' low-level baseline]{.ul} -- Participants were presented with two identical, empty blue rectangles, of the same dimensions as those presented during the encoding and the retrieval conditions and were instructed to simply look at them. ![Graphic representation of the verbal paired associates learning paradigm.](pone.0034858.g001){#pone-0034858-g001} In order to be familiarized with the task, all participants underwent an off-line training session before the fMRI session. Two repetitions of the 4 blocked-conditions were performed, presenting 4 pairs of words per blocked-condition. The words used for the purposes of the training session were different from those presented during scanning. In the analysis, 'blanks' low-level baseline condition was subtracted from all other conditions. In order to isolate mnemonic aspects of encoding and recall processes (and exclude possible effects associated with reading and semantic processing), analysis subtracting the 'fonts' discrimination condition (baseline) from encoding and recall conditions was also performed. Image acquisition {#s2f} ----------------- MR images were obtained using a 1.5 Tesla GE MR Sigma System (GE Medical Systems, Milwaukee, WI, USA) at the Maudsley Hospital, London. For radio frequency transmission and reception, a quadrature birdcage head coil was used. ### fMRI Acquisition {#s2f1} At each of 16 non-contiguous near axial slices (slice thickness = 7 mm, gap = 0.7 mm), 148 T2\-weighted functional images were obtained oriented parallel to the intercommisural (anterior commisure -- posterior commisure) plane so that the whole brain would be covered (repetition time -- TR = 1500 ms, echo time -- TE = 40 ms, flip angle = 70°, 1 excitation, field of view -- FOV = 240^2^ mm, matrix size = 64^2^ mm, in-plane resolution = 3.75^2^ mm, scan time = 735 s). ### Structural MRI Acquisition {#s2f2} A 43 slice high resolution structural image (slice thickness = 3 mm, gap = 0.3 mm, TR = 3000 ms, TE = 40 ms, flip angle = 90°, 8 excitations, FOV = 240^2^ mm, matrix size = 128^2^ mm, in-plane resolution = 1.88^2^ mm, scan time = 72 s) was also collected and used during the normalization of individual functional data into standard Talairach space. A 124 slice, three-dimensional T1-weighted gradient-echo image-sequence allowing for slice reconstruction in any plane (slice thickness = 1.5 mm, TR = 35 ms, TE = 5 ms, flip angle = 35°, 1 excitation, FOV = 240×180 mm, matrix size = 256×128 mm, in-plane resolution = 0.94^2^ mm, scan time = 434 s) was obtained to facilitate structural brain analysis. fMRI data analysis {#s2g} ------------------ ### Individual and group brain mapping {#s2g1} The data were analyzed using the XBAM_v4 software developed at the Institute of Psychiatry, King\'s College London (<http://www.brainmap.it>) [@pone.0034858-Brammer1]. This non-parametric approach, which allows for p values to be estimated accurately with minimal assumptions, was chosen as the most appropriate given the high likelihood of non-parametric distribution in fMRI data [@pone.0034858-Bullmore1]. Data were processed to correct motion, intensity and spin excitation history [@pone.0034858-Bullmore1] and were smoothed prior to statistical analysis and normalization, i.e. in native space. The fMRI voxel dimensions were 3.75 mm in-plane and the slice thickness was 7.7 mm. A Gaussian filter of 8.8 mm FWHM was used, which we deemed appropriate, given the resolution of the images and the likely size of the activated regions. Once pre-processing was completed, single subject analyses in native space were performed. The software detected and modelled blood-oxygen-level dependent (BOLD) responses to each experimental condition using Gamma variate functions (peak responses at 4 and 8 seconds). The sum of squares (SSQ) ratio, a goodness-of-fit statistic was then computed at each voxel. This consisted of the ratio of the sum of squares of deviations from the mean intensity of the image due to the model (model time series) to the sum of squares of deviations due to the residuals (original time series minus model time series). The data were then permuted using a wavelet-based method, which allowed the calculation of the null distribution of SSQ ratios assuming no experimentally determined response [@pone.0034858-Bullmore2]. Individual brain activation maps for each individual for each condition of the task were computed. To reduce the possible confounding effects of differential task performance between the groups on BOLD signal, in each recall block of 8 responses each, only activation related to correct responses was modelled. For instance, if the second and fourth verbal pair was incorrectly recalled, the average recall activation for that block was made up of six rather than 8 stimulus pairs (the model in this example would have estimated 1 0 1 0 1 1 1 1 rather than 1 1 1 1 1 1 1 1). Prior to group analysis, the observed and the randomized SSQ ratio maps (statistical maps) from each individual were transformed into a standard stereotactic space [@pone.0034858-Talairach1]. This was a two-stage procedure; the statistical maps were first realigned to the same individual\'s high resolution structural image and were then normalized to a Talairach template [@pone.0034858-Brammer1]. The Talairach template currently used in XBAM was produced using the Talairach transformation facility of Analysis of Functional Neuroimages (AFNI) software for analysis and visualization of functional magnetic resonance neuroimages [@pone.0034858-Cox1]. Once the individual statistical maps were in Talairach space, group brain activation maps were computed for each task condition. The median of the observed and randomized SSQ ratio maps over all individuals at each voxel was calculated. The distribution of the median of the randomized SSQ ratio maps was then used to obtain the null distribution of SSQ ratios. ### Group comparison {#s2g2} In order to identify brain regions which were differentially activated across the study groups, analysis of variance (ANOVA) was used, testing for a linear trend in regional brain activation where PVH+VD \< UPVH \< normal VPT \< controls and where PVH+VD \> UPVH \> normal VPT \> controls. This model fitted the data at each intracerebral voxel at which all individuals had non-zero data. In order to reduce outlier effects, the model was fitted by minimizing the sum of absolute deviations, rather than the sum of squares. For the computation of the null distribution, group comparison data were permuted under the assumption of no condition or group effect, followed by refitting of the above model. Group comparison maps were produced using XBAM cluster analysis. This is a two-stage procedure using a preliminary voxel level threshold of 0.05 to maximise sensitivity (minimise type II errors), followed by a cluster level threshold, which is chosen to control type I cluster errors at whole brain level. As participants\' age at assessment ranged from 20.75 to 24.58 years, age was used as a covariate in the analyses. SSQ values were extracted from cluster local maxima where differential activation across study groups was evident, in order to be used for graphical representation of the data in the results section. Labels for brain regions with activation local maxima were determined using Talairach coordinates in all stages of the data analysis. Structural MRI data processing and analysis {#s2h} ------------------------------------------- The three-dimensional structural MRI data sets were processed using voxel-based morphometry in Statistical Parametric Mapping SPM8 (Wellcome Department of Cognitive Neurology, Institute of Neurology, London, UK, <http://www.fil.ion.ucl.ac.uspm/software/spm8>), running on Matlab 7.8 (Math-Works, Natick, USA). Initially, images underwent pre-processing consisting of the following stages: 1. Each T1-weighted image was affined-registered into the SPM T1 template and was segmented into different tissue types (i.e. grey and white matter); 2. the affined-registered grey matter images were used to create a customized template using the DARTEL algorithm [@pone.0034858-Ashburner1]; 3. The affined-registered grey matter images were normalized to the customized DARTEL template and were modulated for non-linear components. After the pre-processing, quality check of grey matter segmentation was performed via a sample homogeneity check. Grey matter images were then smoothed with a 12 mm Gausian kernel and used for subsequent statistical analysis. A linear trend whole-brain analysis was performed to examine grey matter volume differences across the four study groups (PVH+VD \< UPVH \< normal VPT \< controls and PVH+VD \> UPVH \> normal VPT \> controls). Grey matter eigenvalues for each study participant were calculated for each cluster where significant between-group differences were observed; SPM\'s 'volume of interest' data extraction tool was used. Structural volume coordinates were originally reported in Montreal Neurological Institute (MNI) space. They were then converted to Talairach space using a Java applet, which employs the Nonlinear Yale MNI to Talairach Conversion Algorithm ([www.bioimagesuite.org](http://www.bioimagesuite.org)) [@pone.0034858-Lacadie1]. Statistical analysis of non-imaging data {#s2i} ---------------------------------------- Statistical analyses were carried out with SPSS v15.0 (SPSS, Chicago, USA). To explore sex, SES and educational level distribution across study groups, a chi-square test for independence (x^2^) was used. Group comparisons in terms of age at assessment, neonatal and neuropsychological data and on-line behavioural measures (those acquired during completion of the fMRI tasks), were performed using one-way univariate ANOVA. Between-group differences in age at assessment were further investigated with post-hoc comparisons using a Games-Howell test. To test the effect of learning on study participants\' performance across the four cued-recall blocks of the verbal paired associates learning task, a one-way repeated measures ANOVA was used. To explore the link between birth-weight and functional data, multiple linear regression analysis was carried out. We used the SSQ values extracted from all regions where differential activation across PVH+VD, UPVH and normal VPT groups and controls were observed, as dependent variables. Birth-weight in grams was entered as predictor in the analysis. In order to investigate the relationship between structural and functional data, multiple linear regression analyses were performed using the SSQ values extracted from all regions where between-group differences were observed, as dependent variables, and grey matter eigenvalues extracted from all regions where structural between-group differences were found, as predictors. Results {#s3} ======= Neuropsychological performance {#s3a} ------------------------------ ANCOVA, controlling for age at assessment, revealed no statistically significant differences in full scale \[F ~(3,\ 50)~ = 1.78, p\>0.05\], verbal \[F ~(3,\ 50)~ = 1.60, p\>0.05\] and performance \[F ~(3,\ 50)~ = 1.39, p\>0.05\] IQ between the PVH+VD, UPVH and normal VPT groups and controls. [Table 2](#pone-0034858-t002){ref-type="table"} displays descriptive statistics for neuropsychological data of the study groups. 10.1371/journal.pone.0034858.t002 ###### Neuropsychological and on-line behavioural data of the study groups. ![](pone.0034858.t002){#pone-0034858-t002-2} Variable[+](#nt104){ref-type="table-fn"} PVH+VD (n = 12) UPVH (n = 17) Normal VPT (n = 12) Controls (n = 17) ------------------------------------------------------------------------ ----------------- ---------------- --------------------- ------------------- Neuropsychological performance (WASI) [a](#nt105){ref-type="table-fn"} Full-scale IQ 105.92 (6.97) 106.47 (9.77) 97.92 (12.43) 107.71 (13.93) Verbal IQ 104.75 (10.07) 102.06 (9.62) 95.67 (13.52) 105.29 (12.12) Performance IQ 106.08 (11.41) 109.06 (10.63) 100.17 (11.26) 108.43 (15) On-line task performance Accuracy (number of correct responses) 27.00 (2.69) 30.35 (2.34) 28.42 (3.73) 28.35 (4.56) Mean and standard deviation (SD) are presented, unless otherwise stated. For controls n = 3 missing data. On-line task performance {#s3b} ------------------------ ANOVA revealed that there were no significant between-group differences in the mean number of correct responses given during the recall condition of the task \[F ~(3,\ 54)~ = 2.31, p\>0.05\]. A one-way repeated-measures ANOVA showed a significant effect of learning, measured in terms of number of correctly recalled words in the cued-recall phase of the task across the four blocks, for all study participants \[F ~(3,\ 55)~ = 32.21, p\<0.001\]. [Table 2](#pone-0034858-t002){ref-type="table"} displays descriptive statistics for on-line task performance of the study groups. Functional MRI results {#s3c} ---------------------- ### Group differences {#s3c1} Linear trend analysis revealed significant differences in regional brain activation across the four study groups, with PVH+VD \< UPVH \< normal VPT \< controls during encoding in the right middle frontal gyrus (Broadmann area -- BA 46) and during recall in the right posterior cingulate gyrus (BA 30), after covarying for age at assessment. There were no statistically significant differences for the opposite contrast i.e. PVH+VD \> UPVH \> normal VPT \> controls. [Table 3](#pone-0034858-t003){ref-type="table"} shows the 3D clusters detected for between-group differences for each condition. [Figure 2](#pone-0034858-g002){ref-type="fig"} displays brain activation maps for between-group differences, as well as graphical displays of the SSQ values in PVH+VD, UPVH and normal VPT groups and controls, as extracted by cluster local maxima were between-group differences were observed. 10.1371/journal.pone.0034858.t003 ###### Between-group differences in regional brain activation during a verbal paired associates learning task. [a](#nt106){ref-type="table-fn"} ![](pone.0034858.t003){#pone-0034858-t003-3} Task condition Brain Region (Broadmann area) Side Talairach Coordinates (x, y, z) Cluster size Cluster p value ------------------------------------------ -------------------------------------------------------------------------------------------------------------------------------- ------ --------------------------------- -------------- ----------------- PVH+VD \< UPVH \< normal VPT \< controls Encoding Middle frontal gyrus (46) extends: anteriorly to right middle frontal gyrus (10) and inferiorly to inferior frontal gyrus (46) R 41, 36, 16 28 0.0051 Recall Posterior cingulate gyrus (30) extends: superiorly to posterior cingulate (31) bilaterally R 14, −62, 13 53 0.0035 Results refer to encoding and recall conditions contrasted with 'fonts discrimination' condition (baseline). ![Between-group differences in regional brain activation during a verbal paired associates learning task.\ Coloured areas signify PVH+VD \< UPVH \< normal VPT \< controls. The numbers at the top of each row of slices represents the z coordinate in Talairach space. The right side of the brain corresponds to the right side of each slice. The graph shows cluster local maxima where differential activation across study groups was observed, as indicated by the mean of SSQ values.](pone.0034858.g002){#pone-0034858-g002} To explore the relationship between birth-weight and SSQ values in brain regions where functional between-group differences were observed, multiple linear regression analysis was performed. Results suggested that birth-weight did not have a significant unique contribution to the prediction of the SSQ values in the right middle frontal gyrus \[F ~(1,\ 39)~ = 0.73, p\>0.05\], and right posterior cingulate gyrus \[F ~(1,\ 39)~ = 0.01, p\>0.05\]. Structural brain differences {#s3d} ---------------------------- Linear trend whole-brain analysis showed significant differences between the four groups in grey matter volume i.e. absolute amount of grey matter, in the right superior temporal gyrus (BA 22), right cerebellum, left middle temporal gyrus (BA 21), right globus pallidus and right medial frontal gyrus (BA 6), where PVH+VD \< UPVH \< normal VPT \< controls (see [Table 4](#pone-0034858-t004){ref-type="table"}). 10.1371/journal.pone.0034858.t004 ###### Between-group differences in grey matter volume. ![](pone.0034858.t004){#pone-0034858-t004-4} Brain Region (Broadmann area) Side Talairach Coordinates (x, y, z) Cluster Size SPM (Z) ------------------------------------------ ------ --------------------------------- -------------- --------- Superior temporal gyrus (22) extends to: R 51, −17, 4 11383 5.38 precentral gyrus (6) R 53, −5, 9 5.07 middle temporal gyrus (22) R 53\. −12, −8 4.80 Cerebellum R 20\. −41, −11 13092 5.26 Middle temporal gyrus (21) L −55, −12, −7 2532 4.87 Globus pallidus extends to: R 17, −11, −3 7678 4.83 thalamus R −7. −8, 16 4.52 Medial frontal gyrus (6) R 22, 3, 50 1376 4.54 Results are FDR (false discovery rate) corrected p\<0.05. Structure-function associations {#s3e} ------------------------------- Multiple linear regression results indicated that structural between-group differences i.e. structural grey matter volume in the right superior temporal gyrus (BA 22), right cerebellum, left middle temporal gyrus (BA 21), right globus pallidus and right medial frontal gyrus (PVH+VD \< UPVH \< normal VPT \< controls) were not significantly associated with functional differences in right middle frontal gyrus (BA 46) \[F ~(5,\ 52)~ = 1.34, p\>0.05\] and in right posterior cingulate gyrus (BA 30) \[F ~(5,\ 52)~ = 1.14, p\>0.05\], where PVH+VD \< UPVH \< normal VPT \< controls during encoding and recall, respectively. Discussion {#s4} ========== This study demonstrates that the adult neuroanatomy of mnemonic processing is modulated by the severity of neonatal brain injury. This occurs in a linear fashion, with those individuals with a history of periventricular haemorhage with associated ventricular dilatation (PVH+VD) displaying the greatest extent of right hypofrontality and decreased right parietal activation during performance of a verbal paired associates learning task compared to the other three groups. In addition, VPT individuals with a history of uncomplicated periventricular haemorrhage (UPVH) show decreased activation compared to VPT individuals with normal ultrasound findings, who, in turn, show reduced activation compared to controls. The study groups (i.e. PVH+VD, UPVH, normal VPT, controls) displayed a comparable on-line performance and achieved comparable scores on measures of IQ and they did not signicantly differ in terms of educational level at assessment. These data are in line with previous fMRI studies describing altered brain activation in VPT young adults in the absence of significant between-group differences in on-line task performance or measures of IQ at assessment [@pone.0034858-Lawrence1], [@pone.0034858-Narberhaus1], [@pone.0034858-Nosarti4]. During encoding, our results identified altered regional brain activation in VPT young adults with differing degrees of neonatal brain injury, where PVH+VD \< UPVH \< normal VPT \< controls, in the right dorsolateral prefrontal cortex (DLPFC), in a cluster with local maxima in right middle frontal gyrus (BA 46), extending ipsilaterally to the middle frontal gyrus (BA 10), and to the inferior frontal gyrus (BA 46). Studies investigating the neuroanatomy underlying the encoding of paired-associates which are subsequently remembered have suggested the involvement of the right DLPFC, possibly due to its role in organizing information in working memory, thereby strengthening associations among items in episodic memory [@pone.0034858-Summerfield1]--[@pone.0034858-Bower1]. During recall, the same pattern of differential activation across the study groups i.e. PVH+VD \< UPVH \< normal VPT \< controls was observed in a cluster with local maxima in the right posterior cingulate gyrus (BA 30), extending bilaterally to posterior cingulate (BA 30 and 31). Lesion studies suggest that damage to the posterior cingulate gyrus may result in loss of verbal episodic memory [@pone.0034858-Valenstein1]. Neuroimaging studies also suggest that this brain region is involved in recall processes of verbal episodic information [@pone.0034858-Petrides1]--[@pone.0034858-Maddock1], possibly due to its strong reciprocal connections with the medial temporal lobe [@pone.0034858-Suzuki1], [@pone.0034858-Morris1]. Taken as a whole, the results of the current study show that regional brain activation decreases with increasing severity of neonatal brain injury in regions mediating verbal paired-associate learning (task-specific regions: posterior cingulate gyrus) and more extensively, in regions subserving working memory, an executive component of the verbal paired associates learning task (DLPFC). Hypoactivity in the DLPFC has been described in developmentally delayed populations, such as individuals with attention deficit hyperactivity disorder (ADHD) during executive-type tasks [@pone.0034858-Dickstein1], [@pone.0034858-Valera1]. Nevertheless, in spite of attenuated activation in these regions, we observed similar levels of on-line task performance in VPT young adults with differing degrees of neonatal brain injury and controls. This may be because the studied task was relatively easy to perform, as we wished to ensure all participants would be able to complete it during the scanning session. Behavioural differences may become apparent with increasing cognitive load, when VPT individuals with differing degrees of neonatal brain injury may fail to optimally engage task specific areas and more general 'executive' brain areas, which could result in impaired task performance [@pone.0034858-Nosarti2], [@pone.0034858-Downie1], [@pone.0034858-Luu1]. Non-significant between-group differences in on-line task performance may also be accounted for by a ceiling effect. In addition, it is possible that fMRI techniques are particularly sensitive in detecting differences at the neuronal activation level between small groups of participants, like those included in the current study, whereas behavioural analyses require larger groups to provide reliable results [@pone.0034858-Friston1], [@pone.0034858-Nosarti5]. Differences in neuronal activation between the groups may be partly explained by structural brain changes associated with very preterm birth and neonatal brain injuries [@pone.0034858-Gimenez2], [@pone.0034858-Lawrence1]. This study investigated participants\' structural MRI data, which was analysed in the same way as the fMRI data, i.e. with linear trend analysis. Voxel based morphometry revealed significant between-group differences in grey matter volume in the right superior temporal gyrus, right cerebellum, left middle temporal gyrus, right globus pallidus and right medial frontal gyrus, where the PVH+VD group showed the greatest decreases compared to the other three groups. This finding is consistent with previous studies reporting the greatest alterations in grey matter and white matter volume in VPT individuals with a history of severe neonatal brain injury (i.e. PVH+VD) [@pone.0034858-Nosarti1], [@pone.0034858-Nosarti3]. Additionally, this pattern of structural abnormalities, which includes the temporal and frontal cortices, the cerebellum and the globus pallidus has been observed in neurodevelopmental disorders such as ADHD [@pone.0034858-Castellanos1], [@pone.0034858-Castellanos2]. When investigating the relationship between participants\' structural volume in the regions listed above where significant between-group differences were observed and functional MRI results, we did not detect a statistically significant association. This is in contrast to previous studies in similar samples, where we observed that structural differences between the groups accounted for a small percentage of the variance of fMRI results [@pone.0034858-Narberhaus1], [@pone.0034858-Nosarti4]. Our current results suggest that in this instance between-group differences in regional brain activation may not be solely interpreted in the context of structural brain alterations [@pone.0034858-Langenecker1]. However, we cannot rule out that differences in neuronal activation between the groups may be associated with cytoarchitectonic changes in the brain regions where structural between group differences were observed (as well as in others which are known to be affected by neonatal brain injury) [@pone.0034858-Allin2], [@pone.0034858-Kuban1], which could not be studied with the methods of structural analysis we used in this study. Preterm birth has in fact been associated with abnormalities in neural architecture and connectivity [@pone.0034858-Lubsen1]. A limitation of this study is that the fMRI data reported here may not be generalizable to VPT populations -- for example VPT young adults who have compromised cognitive function were not studied. Additionally, we have not collected any data on other factors that may have contributed to fMRI differences among the study groups, such as family history of psychiatric disorders and maltreatment during development. Other limitations include the age difference between VPT participants with a history of neonatal brain injury (PVH+VD, UPVH) and VPT participants with normal ultrasonographic findings and controls. The majority of the participants belonging to these two latter groups (see Methods sections) were scanned at an earlier time point i.e. approximately 5 years before the PVH+VD and UPVH groups, due to logistic reasons. We, however, controlled for age at assessment in the fMRI data analyses. Further limitations arise from the use of a previously scanned normal VPT and control group and relate to possible implications of scanner variation over time. Nevertheless, fMRI experiments measure changes in BOLD signal, which is less affected by hardware changes as it relies on an innate contrast mechanism between experimental conditions and a baseline. Quality control of the fMRI data acquired throughout the time of the two studies was also carried out to identify variations of BOLD signal intensity using an automated data processing scheme and Shewhart charting [@pone.0034858-Simmons1]. Finally, the sole use of a linear trend analysis of the fMRI data acquired during performance of the verbal paired associates learning task could have limited the identification of brain regions where differential activation might have only been present in pair-wise analyses. A similar limitation applies to the analysis of the structural data, which were analyzed using a linear trend approach. To summarise, the results of this study suggest that increased severity of early brain injury is associated with decreased neural recruitment in regions mediating verbal paired-associate learning (i.e. posterior cingulate gyrus) and in regions postulated to be involved in more general 'executive-type' processing (i.e. DLPFC). Although the current study did not detect significant differences in on-line task performance between the groups, the sub-optimal neural engagement of task-specific and of 'executive' brain regions in VPT individuals, and especially in those with severe early injury, poses the question whether behavioural differences may become apparent with increasing cognitive load, which will be the focus of future studies. The authors wish to thank Professor Mick Brammer and Mr. Jeffrey Dalton for providing us with scientific advice, Dr. Colin O\'Carroll for his help with data collection, Mr. David Gasston for his assistance in formatting the figures, and all participants for their on-going cooperation. We also thank Cerebra and the NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and Institute of Psychiatry, Kings College London for their continuing support. Competing Interests:The authors have declared that no competing interests exist. Funding:The study was funded by the Cerebra Foundation for The Brain Injured Infant (CN and RMM). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. [^1]: Conceived and designed the experiments: CN VG PM RMM LR MPA. Performed the experiments: AKK. Analyzed the data: AKK KN VG CN. Contributed reagents/materials/analysis tools: VG KN AKK CN. Wrote the paper: AKK CN RMM. Conceptual design of the study: CN PM RMM LR MPA. Provided help with participants\' recruitment: MW.	{ "pile_set_name": "PubMed Central" }
ROY KEANE has accused Sir Alex Ferguson of still trying to exert “control and power” at Manchester United – and says that his “massive ego” is undermining David Moyes. HAPPIER TIMES: Keane with the United manager. Ferguson can't resist keeping an eye on team matters [GETTY] Ferguson retired after last season and Moyes, the man he chose to replace him, is struggling. Moyes faces another test tonight when United take on Shakhtar Donetsk at home in the Champions League. Ferguson is now a United director and Keane said: “Everything is about control and power. He’s still striving for it now even though he’s not the manager. There’s massive ego involved in that.” Keane, who left United in 2005 after a fall-out with Ferguson, said his relationship with his former manager was “non-existent” and that Ferguson’s strongest trait was his “ruthlessness”, while labelling “loyalty” his biggest weakness. And Keane twisted the knife further by claiming Brian Clough was the best manager he worked under. His comments follows revelations by Ferguson in his autobiography of the row that forced Keane out of United. Related articles I did shed a few tears in my car for about two minutes. I could have easily played for United for another couple of years Roy Keane Keane admitted he “cried” when he left abruptly over a candid interview he gave to the club’s in-house television station criticising his team-mates. “Of course I was upset,” Keane said. “I did shed a few tears in my car for about two minutes. I could have easily played for United for another couple of years.” Keane claimed that he felt the row between Ferguson and former shareholders John Magnier and JP McManus over the stud rights to racehorse Rock of Gibraltar had a “negative effect” on the club. He said: “If people didn’t think (the Rock of Gibraltar row) had a negative effect on the club then they are in cuckoo land.” Meanwhile another former United star, Ray Wilkins, has accused the current players of being scared to receive the ball in Saturday’s 1-0 home defeat to Newcastle. “For the first time on Saturday, I saw Manchester United players not wanting the ball, which is unheard of at Old Trafford.”	{ "pile_set_name": "Pile-CC" }
Ab Ghamushiyeh Ab Ghamushiyeh (, also Romanized as Āb Ghāmūshīyeh) is a village in Khabar Rural District, in the Central District of Baft County, Kerman Province, Iran. At the 2006 census, its population was 21, with 5 families. References Category:Populated places in Baft County	{ "pile_set_name": "Wikipedia (en)" }
1. Field of the Invention In general, the present invention relates to the production of zeolites. 2. Description of the Prior Art Certain naturally occurring hydrated metal aluminum silicates are called zeolites. The synthetic zeolites of the invention have compositions similar to some of the natural zeolites. The most common of these zeolites are sodium zeolites. Zeolites consist basically of a three-dimensional framework of SiO.sub.4 and AlO.sub.4 tetrahedra. The tetrahedra are cross-linked by the sharing of oxygen atoms so that the ratio of oxygen atoms to the total of the aluminum and silicon atoms is equal to two or O/(Al+Si)=2. The electrovalence of each tetrahedra containing aluminum is balanced by the inclusion in the crystal of a cation, for example, a sodium ion. This balance may be expressed by the formula, Al/Na=1. The spaces between the tetrahedra are occupied by water molecules prior to dehydration. Zeolites may be activated by heating to effect the loss of the water of hydration. The dehydration results in crystals interlaced with channels of molecular dimensions that offer very high surface areas for the adsorption of foreign molecules. The interstitial channels of zeolite X are of a size such that heptacosafluorotributylamine and larger molecules will not enter into the channels. The interstitial channels of zeolite A will not accept molecules larger than 5.5 A. Zeolites A and X may be distinguished from other zeolites and silicates on the basis of their x-ray powder diffraction patterns and certain physical characteristics. The x-ray patterns for several of these zeolites are described below. The composition and density are among the characteristics which have been found to be important in identifying these zeolites. The basic formula for all crystalline sodium zeolites may be represented as follows: Na.sub.2 O:Al.sub.2 O.sub.3 :xSiO.sub.2 :yH.sub.2 O PA1 1.0.+-.0.2Na.sub.2 O:Al.sub.2 O.sub.3 :1.85.+-.0.5SiO.sub.2 :yH.sub.2 O In general, a particular crystalline zeolite will have values for x and y that fall in a definite range. The value x for a particular zeolite will vary somewhat since the aluminum atoms and the silicon atoms occupy essentially equivalent positions in the lattice. Minor variations in the relative numbers of these atoms do not significantly alter the crystal structure of physical properties of the zeolite. For zeolite X, an average value for x is about 2.5 with the x value normally falling within the range 2.5.+-.0.5. For zeolite A, the x value normally falls within the range 1.85+0.5. The value of y is not necessarily an invariant for all samples of zeolites. This is true because various exchangeable ions are of different size, and, since there is no major change in the crystal lattice dimensions upon ion exchange, the space available in the pores of the zeolite to accommodate water molecules varies. The average value for y determined for zeolite X is 6.2. For zeolite A, it is 5.1. In zeolites synthesized according to the preferred procedure, the molar ratio Na.sub.2 O/Al.sub.2 O.sub.3 should equal one. But if all the excess sodium present in the mother liquor is not washed out of the precipitated product, analysis may show a ratio greater than one, and if the washing is carried too far, some sodium may be ion exchanged by hydrogen, and the ratio will drop below one. It has been found that due to the ease with which hydrogen exchange takes place, the ratio for zeolite X lies in the range of EQU Na.sub.2 O/Al.sub.2 O.sub.3 =0.9.+-.0.2. The ratio for zeolite A lies in the range of EQU Na.sub.2 O/Al.sub.2 O.sub.3 =1.0.+-.0.2. Thus, the formula for zeolite A may be written as follows: The formula for zeolite X may be written as follows: 0.9.+-.0.2Na.sub.2 O:Al.sub.2 O.sub.3 :2.5.+-.0.5SiO.sub.2 :yH.sub.2 O "y" May be any value up to 6 for zeolite A; any value up to 8 for zeolite X. The pores of zeolites normally contain water. The above formulas represent the chemical analysis of zeolites A and X. When other materials as well as water are in the pores, chemical analysis will show a lower value of y and the presence of other adsorbates. The presence in the crystal lattice of materials volatile at temperatures below about 600.degree. C. does not significantly alter the usefulness of the zeolites as an adsorbent since the pores are usually freed of such volatile materials during activation. Among the ways of identifying zeolites and distinguishing them from other zeolites and other crystalline substances, the X-ray powder diffraction pattern has been found to be a useful tool. In obtaining the X-ray powder diffraction patterns, standard techniques are employed. The radiation is the K.alpha. doublet of copper, and a Geiger counter spectrometer with a strip chart pen recorder is used. The peak heights, I, and the positions as a function of 2.theta. where .theta. is the Bragg angle, were read from a spectrometer chart. From these, the relative intensities, 100 I/I.sub.o, where I.sub.o is the intensity of the strongest line or peak, and d the interplanar spacing in A corresponding to the recorded lines were calculated. X-ray powder diffraction data for sodium zeolite X are given in Table A. 100 I/I.sub.o and the d values in angstroms (A) for the observed lines for zeolite X are also given. The X-ray patterns indicate a cubic unit cell of dimensions between 24.5 A and 25.5 A. In a separate column are listed the sum of the squares of the Miller indices (h.sup.2 +k.sup.2 +l.sup.2) for a cubic unit cell that corresponds to the observed lines in the x-ray diffraction patterns. The a.sub.o value for zeolite X is 24.99 A where a.sub.o is the unit cell edge. Zeolite X is a name given to a synthetic zeolite having the crystal structure of the naturally occurring mineral, faujasite. Zeolite X is the name for those compounds having an SiO.sub.2 /Al.sub.2 O.sub.3 ratio of less than 3. TABLE A ______________________________________ X-RAY DIFFRACTION PATTERN FOR ZEOLITE X h.sup.2 + k.sup.2 + l.sup.2 ##STR1## d (A) ______________________________________ 3 100 14.47 8 18 8.85 11 12 7.54 19 18 5.73 27 5 4.81 32 9 4.42 35 1 4.23 40 4 3.946 43 21 3.808 44 3 3.765 48 1 3.609 51 1 3.500 56 18 3.338 59 1 3.253 67 4 3.051 72 9 2.944 75 19 2.885 80 8 2.794 83 2 2.743 88 8 2.663 91 3 2.620 96 1 2.550 108 5 2.404 123 1 2.254 128 3 2.209 131 3 2.182 136 2 2.141 139 2 2.120 144 1 2.083 164 1 1.952 168 1 1.928 184 1 1.842 195 1 1.789 200 2 1.767 211 3 1.721 243 3 1.603 ______________________________________ The more significant d values for zeolite X are given in Table B. TABLE B ______________________________________ MOST SIGNIFICANT d VALUES FOR ZEOLITE X d Value of Reflection in A ______________________________________ 14.42 .+-. 0.2 8.82 .+-. 0.1 4.41 .+-. 0.05 3.80 .+-. 0.05 3.33 .+-. 0.05 2.88 .+-. 0.05 2.79 .+-. 0.05 2.66 .+-. 0.05 ______________________________________ X-ray powder diffraction data for sodium zeolite A are given in Table C. TABLE C ______________________________________ X-RAY DIFFRACTION PATTERN FOR ZEOLITE A h.sup.2 + k.sup.2 + l.sup.2 d (A) ##STR2## ______________________________________ 1 12.29 100 2 8.71 70 3 7.11 35 4 6.15 2 5 5.51 25 6 5.03 2 8 4.36 6 9 4.107 35 10 3.895 2 11 3.714 50 13 3.417 16 14 3.293 45 16 3.078 2 17 2.987 55 18 2.904 10 20 2.754 12 21 2.688 4 22 2.626 20 24 2.515 6 25 2.464 4 26 2.414 >1 27 2.371 3 29 2.289 1 30 2.249 3 32 2.177 7 33 2.144 10 34 2.113 3 35 2.083 4 36 2.053 9 41 1.924 7 42 1.901 4 44 1.858 2 45 1.837 3 49 1.759 2 50 1.743 13 53 1.692 6 54 1.676 2 55 1.661 2 57 1.632 4 59 1.604 6 ______________________________________ The more significant d values for zeolite A are given in Table D. TABLE D ______________________________________ MOST SIGNIFICANT d VALUES FOR ZEOLITE A d Value of Reflection in A ______________________________________ 12.2 .+-. 0.2 8.7 .+-. 0.2 7.10 .+-. 0.15 5.50 .+-. 0.10 4.10 .+-. 0.10 3.70 .+-. 0.07 3.40 .+-. 0.06 3.29 .+-. 0.05 2.98 .+-. 0.05 2.62 .+-. 0.05 ______________________________________ Occasionally, additional lines not belonging to the pattern for the zeolite appear in a pattern along with the X-ray lines characteristic of that zeolite. This is an indication that one or more additional crystalline materials are mixed with the zeolite in the sample being tested. Frequently these additional materials can be identified as initial reactants in the synthesis of the zeolite, or as other crystalline substances. When the zeolite is heat treated at temperatures of between 100.degree. C. and 600.degree. C. in the presence of water vapor or other gases or vapors, the relative intensities of the lines in the X-ray pattern may be appreciably changed from those existing in the unactivated zeolite patterns. Small changes in line positions may also occur under these conditions. These changes in no way hinder the identification of these X-ray patterns as belonging to the zeolite. The particular X-ray technique and/or apparatus employed, the humidity, the temperature, the orientation of the powder crystals and other variables, all of which are well known and understood to those skilled in the art of X-ray crystallography or diffraction can cause some variations in the intensities and positions of the lines. These changes, even in those few instances where they become large, pose no problem to the skilled X-ray crystallographer in establishing identities. Thus, the X-ray data given herein to identify the lattice for a zeolite are not to exclude those materials which, due to some variable mentioned or otherwise known to those skilled in the art, fail to show all of the lines, or show a few extra ones that are permissible in the cubic system of that zeolite, or show a slight shift in position of the lines, so as to give a slightly larger or smaller lattice parameter. A simple test described in "American Mineralogist", Vol. 28, page 545, 1943, permits a quick check of the silicon to aluminum ratio of the zeolite. According to the description of the test, zeolite minerals with a three-dimensional network that contains aluminum and silicon atoms in an atomic ratio of Al/Si=2/3=0.67, or greater, produce a gel when treated with hydrochloric acid. Zeolites having smaller aluminum to silicon ratios disintegrate in the presence of hydrochloric acid and precipitate silica. U.S. Pat. No. 2,882,243 describes a process for making zeolite A comprising preparing a sodium-aluminum-silicate water mixture having an SiO.sub.2 /Al.sub.2 O.sub.3 mole ratio of from 0.5:1 to 2.5:1, an Na.sub.2 O/SiO.sub.2 mole ratio of from 0.8:1 to 3:1, and an H.sub.2 O/Na.sub.2 O mole ratio of from 35:1 to 200:1, maintaining the mixture at a temperature of from 20.degree. C. to 175.degree. C. until zeolite A is formed, and separating the zeolite A from the mother liquor. U.S. Pat. No. 2,882,244 describes a process for making zeolite X comprising preparing a sodium-aluminum-silicate water mixture having an SiO.sub.2 /Al.sub.2 O.sub.3 mole ratio of from 3:1 to 5:1, an Na.sub.2 O/SiO.sub.2 mole ratio of from 1.2:1 to 1.5:1, and an H.sub.2 O/Na.sub.2 O mole ratio of from 35:1 to 60:1, maintaining the mixture at a temperature of from 20.degree. C. to 120.degree. C. until zeolite X is formed and separating the zeolite X from the mother liquor. The process described in U.S. Pat. No. 3,101,251 is similar to that described in U.S. Pat. Nos. 2,882,243 and 2,882,244, except that the reaction mixture contains an admixture of non-kaolinitic alumino-silicate mineral and sodium hydroxide that has been fused at a temperature of between 330.degree. C. and 370.degree. C. In U.S. Pat. No. 3,119,659, a kaolin clay and sodium hydroxide are formed into a compact body, dried, reacted in an aqueous mixture at a temperature of from 20.degree. C. to 175.degree. C. until a zeolite is formed. Zeolite A is formed in a reaction mixture having an Na.sub.2 O/SiO.sub.2 molar ratio of 0.5:1 to 1.5:1, an SiO.sub.2 /Al.sub.2 O.sub.3 molar ratio of 1.6:1 to 2.4:1 and an H.sub.2 O/Na.sub.2 O molar ratio of 20:1 to 100:1. Zeolite X is formed in a reaction mixture having an Na.sub.2 O/SiO.sub.2 molar ratio of 1.5:1, an SiO.sub.2 /Al.sub.2 O.sub.3 molar ratio of 5:1, and an H.sub.2 O/Na.sub.2 O molar ratio of 30:1 to 60:1. U.S. Pat. No. 4,235,856 discloses a process for making a combination of zeolite X and zeolite A wherein a sodium aluminate solution is added to a sodium silicate solution to form a mixture, then heating and reacting the mixture to 80.degree.-120.degree. C. until the combination zeolite is formed. Another patent which discloses a process for making synthetic zeolite particles having two different sized effective pore entrance diameters within a single particle, namely a particle containing both a Type A zeolite structure and a Type X zeolite structure is U.S. Pat. No. 3,366,578. U.S. Pat. No. 4,094,778 discloses a process for sequestering calcium and magnesium cations using mixtures of zeolite A and zeolite X. British Pat. No. 1,533,496 sets forth a process for preparing low silica faujasite-type zeolites by adding potassium hydroxide or a potassium salt to the alumina trihydrate in addition to the sodium hydroxide prior to the addition of the sodium silicate. U.S. Pat. No. 4,166,099 discloses a method for preparing crystalline aluminosilicates, such as a Type X synthetic faujasite by seeding an alkaline precursor mixture of alumina and silica with small size zeolite seeds having an average particle size below about 0.1 micron. Zeolites are useful as molecular sieves and as sequestering agents for calcium and magnesium cations. They are particularly useful in detergent or washing compositions. It is a primary object of the present invention to provide a faster and more economical process for making combination zeolite X and zeolite A particles.	{ "pile_set_name": "USPTO Backgrounds" }
Non-invasive coronary flow reserve after successful primary angioplasty for acute anterior myocardial infarction is an independent predictor of left ventricular adverse remodelling. To assess the usefulness of non-invasive coronary flow reserve (CFR) to predict left ventricular adverse remodelling (LVR) after ST-elevation myocardial infarction (STEMI). Sixty-five consecutive patients (mean age 58 +/- 13 years, 24 women) with a first anterior STEMI, underwent prospectively CFR in the distal part of the left anterior descending artery (LAD), using intravenous adenosine infusion (0.14 mg/kg/min, within 2 min), and a standard echocardiography during the same exam, performed within 24 h after successful primary coronary angioplasty, and 6 months later, while the patients were in stable haemodynamic situation. CFR was defined as the peak hyperaemic LAD flow velocity divided by the baseline flow velocity. LV end-systolic volume (ESV) and end-diastolic volume (EDV), and LV ejection fraction (LVEF) were measured using the biplane Simpson's rule. LVR was defined as an absolute increase of ESV > or =15%. Compared with patients without LVR, patients with LVR (n = 18) had higher peak troponin T levels, wall motion score (WMS), a worse initial angiographic TIMI flow grade, and less improved electrocardiographic ST-segment resolution (all P < 0.05), and lower CFR (1.43 +/- 0.2 vs. 1.97 +/- 0.5, P < 0.01). At 6 months, patients with LVR had higher WMS, ESV, EDV, and lower LVEF compared with patients without LVR (all P < 0.01). Furthermore, acute CFR was significantly correlated to the 6-month LVEF and ESV, and to change of LVEF and ESV (all P < 0.01). In the multivariate analysis, acute CFR and initial angiographic TIMI flow grade were the independent predictors of LVR (all P < or = 0.01). Receiver-operating characteristic curve analysis demonstrated that a cut-off value of 1.7 for CFR yields a sensitivity of 100% and a specificity of 62% to predict LVR at follow-up (P < 0.001, area under the curve 0.82). Non-invasive CFR is an independent predictor of LVR after successful primary angioplasty of anterior STEMI.	{ "pile_set_name": "PubMed Abstracts" }
// // Copyright (c) 2020 Related Code - http://relatedcode.com // // THE SOFTWARE IS PROVIDED "AS IS", WITHOUT WARRANTY OF ANY KIND, EXPRESS OR // IMPLIED, INCLUDING BUT NOT LIMITED TO THE WARRANTIES OF MERCHANTABILITY, // FITNESS FOR A PARTICULAR PURPOSE AND NONINFRINGEMENT. IN NO EVENT SHALL THE // AUTHORS OR COPYRIGHT HOLDERS BE LIABLE FOR ANY CLAIM, DAMAGES OR OTHER // LIABILITY, WHETHER IN AN ACTION OF CONTRACT, TORT OR OTHERWISE, ARISING FROM, // OUT OF OR IN CONNECTION WITH THE SOFTWARE OR THE USE OR OTHER DEALINGS IN // THE SOFTWARE. import UIKit //------------------------------------------------------------------------------------------------------------------------------------------------- class Walkthrough5Cell: UICollectionViewCell { @IBOutlet var imageView: UIImageView! @IBOutlet var labelFeature1: UILabel! @IBOutlet var labelDescription1: UILabel! @IBOutlet var labelFeature2: UILabel! @IBOutlet var labelDescription2: UILabel! //--------------------------------------------------------------------------------------------------------------------------------------------- func bindData(index: Int, data: [String: String]) { guard let feature1 = data["feature1"] else { return } guard let description1 = data["description1"] else { return } guard let feature2 = data["feature2"] else { return } guard let description2 = data["description2"] else { return } imageView.sample("Finance", "Accounting", index + 5) labelFeature1.text = feature1 labelDescription1.text = description1 labelFeature2.text = feature2 labelDescription2.text = description2 } }	{ "pile_set_name": "Github" }
271 F.Supp.2d 64 (2002) Jerome CANADY, M.D. and Argon Electro-Surgical Corp., Plaintiffs, v. ERBE ELEKTROMEDIZIN GMBH and Erbe U.S.A., Defendants. No. CIV.A. 96-2012(RMU). United States District Court, District of Columbia. July 31, 2002. 65 Timothy R. DeWitt, Arnold & Porter, McLean, VA, Counsel for the plaintiffs. Martin Paul Hoffman, Hoffman, Wassen & Gitler, Arlington, VA, Co-counsel for the defendants. Nate F. Scarpelli, Marshall, O'Toole, Gerstein, Murray & Borun, Chicago, IL, Co-counsel for the defendants. MEMORANDUM OPINION URBINA, District Judge. DENYING THE PLAINTIFFS' MOTION TO LIFT THE STAY I. INTRODUCTION This matter is before the court on the plaintiffs' motion to lift the stay imposed by this court on July 28, 2000 pending the outcome of reexamination proceedings before the U.S. Patent and Trademark Office ("PTO"). U.S. Patent Number 5,207,675 ("the 675 patent"), the patent at issue in this action, describes an electrosurgical[1] device capable of facilitating blood coagulation[2] during surgical procedures. The 66 plaintiffs, Jerome Canady and Argon Electro-Surgical Corporation, own the 675 patent. The defendants, Erbe U.S.A. and its German parent corporation, Erbe Elektromedizin GmbH, manufacture and sell several models of a similar electrosurgical device known as an argon plasma coagulation ("APC") probe. The plaintiffs seek to lift the stay asserting that by filing a total of three requests for reexamination, the defendants are using PTO proceedings for dilatory purposes, and that continuing the stay presents a tactical disadvantage to the plaintiffs. The defendants counter that the filing of multiple requests for reexamination is proper where the submissions in those requests raise a new question of patentability. Although the PTO has already reviewed the first request for reexamination, it has granted two additional requests for reexamination filed by the defendants on September 24, 2001 and October 12, 2001 respectively. The PTO has merged those additional requests and is currently undergoing reexamination proceedings. The defendants correctly indicate that the PTO's determination is expected to narrow or resolve many issues in this litigation. Consequently, since the PTO has not rendered a final decision regarding the validity of the plaintiffs' 675 patent, and the plaintiffs have not sufficiently demonstrated that they will suffer a tactical disadvantage as a result of sustaining the stay, the court denies the plaintiffs' motion to lift the stay as not ripe for adjudication. II. BACKGROUND A. Factual Background This litigation is the result of a chance meeting of the parties at the "Minimally Invasive Surgery Conference" held in Luxemburg in 1992. Am. Compl. ¶¶ 10-13. At that conference, defendant Erbe Elektromedizin GmbH had a booth demonstrating a new device, the APC, to members of the medical field. Id. Plaintiff Canady happened upon this booth and notified defendant Erbe Elektromedizin of his own similar invention that had been filed with the PTO for patent on July 15, 1991. Id. Subsequent communications between the parties revealed that plaintiff Canady's patent was filed first in time and the present litigation ensued. Id. Initially, plaintiff Canady claimed patent infringement by the defendants. Compl. ¶ 12. The defendants counterclaimed that there was no infringement and that plaintiff Canady's patent was invalid because prior art showed that the device was "obvious"[3] and merely the combination of two previous patents, Manwaring (U.S. Patent No. 5,122,138 (issued June 16, 1992)) and McGreevy (U.S. Patent No. 4,781,175 (issued November 1, 1988)). Defs.' Counterclaim ¶¶ 23-25. As the case progressed, Argon-Electrosurgical Corp. was joined as a plaintiff on July 14, 1997 when it obtained co-ownership of the 675 patent. Order dated July 14, 1997. On June 21, 2000, the defendants filed a request for reexamination of the 675 patent 67 with the PTO asserting that substantial new questions of patentability of claims 1 and 7-16 of the 675 patent were raised by certain references not considered by the PTO in plaintiff Canady's patent application. Defs.' Mot. for Stay at 1; Pls.' Mot. to Lift Stay ("Pls.' Mot.") Ex. D. As a result of this request the court entered a stay on July 28, 2000 pending the outcome of the PTO's reexamination. The PTO granted the defendants' first request for reexamination on September 12, 2000 finding a "substantial new question of patentability" affecting claims 1 and 7-16 of the 675 patent. Defs.' Opp'n Ex. 2 at 2.[4] On November 7, 2000, plaintiff Canady filed a patent owner's statement pursuant to the reexamination procedure, opposing the defendants' first request for reexamination and the PTO's decision to grant that request. Id. Plaintiff Canady submitted to the PTO a self-declaration under 37 C.F.R. § 1.132 supporting his position that no substantial questions of patentability were raised by the references submitted by the defendants. Id. On January 8, 2001, the defendants filed their requestor's reply to plaintiff Canady's patent owner's statement. Id. In response to the arguments in the November 7, 2000 patent owner's statement and the requestor's reply, the PTO issued an office action[5] on June 24, 2001, rejecting plaintiff Canady's claims 1, 2, and 7-16 as unpatentable. Id. (citing Ex. 6 (the PTO's office action, dated June 24, 2001)). Plaintiff Canady then filed a response opposing the PTO's rejection of claims, relying in part on his supplemental declaration under 37 C.F.R. § 1.132. Pls.' Mot. Ex. F. The plaintiffs assert that they did not seek to lift the stay at that time because they believed the submission of this response would resolve the adverse decision by the PTO, thereby allowing the present litigation to continue. Pls.' Mot. at 2. Since the parties updated the court on the status of this case on August 24, 2001, however, several developments have transpired, both in the PTO's reexamination of the patent and otherwise, which the plaintiffs believe significantly change the circumstances that existed at the time this court entered the stay and which now justify lifting the stay. Id. Specifically, on September 24, 2001, the defendants filed a second request for reexamination, bringing to the PTO's attention two references that were not considered by the PTO either during its initial examination of plaintiff Canady's patent application or during its reexamination pursuant to the defendants' first request. Pls.' Mot. Ex. L. The defendants believe these references (1) refute unsupported and unsupportable factual allegations made in plaintiff Canady's response to the June 24, 2001 office action and in plaintiff Canady's supplemental declaration, and (2) will raise substantial new questions of patentability of the 675 patent when reviewed by the PTO. Defs.' Opp'n at 4. The defendants state that they filed the second request promptly after discovering the two relevant references, assuring that the PTO would have these references available for consideration before issuing another office action in reexamination. Id. This task accomplished, the defendants continued to search for additional references to refute plaintiff Canady's arguments and render the 675 patent invalid. Id. 68 The defendants uncovered additional references shortly after they filed their second request. Pls.' Mot. Ex. M. Accordingly, on October 12, 2001, they filed a third request for reexamination, submitting six additional references not considered in any other PTO proceeding. Id. The defendants assert that they did not violate the PTO's reexamination process because they filed their request promptly. Defs.' Opp'n at 15-21. The PTO granted both the defendants' second and third requests on November 29, 2001 after determining that the references when combined with other submissions in the record "raise a substantial new question of patentability." Id. at 6. Plaintiff Canady's opportunity to file a patent owner's statement expired on January 29, 2002. Id. Moreover, plaintiff Canady has not challenged the PTO's decision to grant reexamination by filing a petition with the PTO's Director. Defs.' Opp'n at 6; 37 C.F.R. § 1.182. On June 17, 2002, the PTO merged the second and third accepted requests under 37 C.F.R. § 1.565. Defs.' Status Report dated June 17, 2002 (including the PTO's decision to merge, dated June 17, 2002). 1. The PTO's Reexamination As a result of the high costs of enforcing patent rights, Congress passed the Patent Act of 1980, as amended, 35 U.S.C. §§ 301-07. The purpose of the Patent Act is to allow the reexamination of patent validity in an impartial forum at almost 100 times less cost to the parties by people trained to understand the technologies described in patents. H.R.Rep. No. 1307, 96th Cong., 2d Sess., pt. 7 at 4 (1980) (enacted), reprinted in 1980 U.S.C.C.A.N. 6460. In fact, courts often stay proceedings, such as in the instant case, to wait for reexamination results that will simplify litigation by eliminating, clarifying, or limiting the claims. Ethicon v. Quigg, 849 F.2d 1422, 1428 (Fed.Cir.1988). The Manual of Patent Examining Procedure ("MPEP") outlines the process of reexamination drawing from Title 35 of the United States Code, Title 37 of the Code of Federal Regulations, and the PTO's own practices. Although the Federal Circuit has not expressly adopted the MPEP, the Federal Circuit generally follows the MPEP. Patlex Corp. v. Mossinghoff, 758 F.2d 594, 606 (Fed.Cir.1985) (citing In re Kaghan, 55 C.C.P.A. 844, 387 F.2d 398, 401 (Cust. & Pat.App.1967) (determining that appellants can rely on procedures outlined by the MPEP)). Reexamination of a patent is initiated when one files a request for reexamination with the PTO regarding the invalidity of any claim in a patent on the basis of prior art. 35 U.S.C. § 302. Prior art consists of patents or printed publications, which are believed to bear on the patentability of any claim in a particular patent. 35 U.S.C. § 301. Where references are submitted to demonstrate that the invention is unpatentable for obviousness (such as in this case), the PTO considers those works as a whole and must demonstrate the desirability and obviousness at the genesis of the invention. 35 U.S.C. § 103; Hodosh v. Block Drug Co., 786 F.2d 1136, 1143 (Fed.Cir.1986). Furthermore, the strength of the references submitted is gauged at the time of the invention, not in hindsight. Id. The PTO grants reexamination when a request demonstrates a "substantial new question of patentability" through patents or prior publications. 35 U.S.C. § 303(a); 37 C.F.R. § 1.515(a); M.P.E.P. § 2240. If the PTO grants reexamination, the PTO will "expidite[] to the extent possible" the reexamination proceedings following receipt of the statement by the patent owner under 37 C.F.R. § 1.530 and the reply by the requestor under 37 C.F.R. § 1.535. M.P.E.P. § 2241. The PTO states that a grant of reexamination need only establish 69 a substantially new question of patentability as to any one of the patent's claims, even if the request for reexamination does not question that claim. M.P.E.P. § 2242. Upon a determination by the PTO to grant reexamination, the reexamination itself is conducted ex parte. 37 C.F.R. § 1.550(a). The patent owner is given a reasonable period to respond, including any amendments to the patent and new claim(s) the owner may wish to propose. Id. If the patent owner files a response and serves it on the requestor, the requestor will then be allowed to reply to that statement within two months. Id. After the filing of the patent owner's statement and the requestor's reply, or the time for filing has expired, the reexamination proceeding will continue. 35 U.S.C. § 305; M.P.E.P. § 2254. The patent owner will then have an opportunity to respond to any new rejection before the finalization of the PTO's proceedings in a final office action. 37 C.F.R. § 1.570; M.P.E.P. § 2271. Where a second or subsequent request for reexamination is filed concurrent with an existing reexamination, as is the case herein, the PTO will determine the presence of a substantial new question of patentability in the second or subsequent request. M.P.E.P. § 2240. If the second request is filed within three months of the first request, the PTO may merge those requests, as was done in this case. 37 C.F.R. § 1.565. The patent owner may petition the PTO to deny the request for reexamination under 37 C.F.R. § 1.182 if the second or subsequent request is filed in an effort to harass or delay pending litigation. M.P.E.P. § 2240. Where the PTO combines the reexamination proceedings, the PTO will issue a single certificate and office action based on the combined proceedings. 37 C.F.R. § 1.565(c). 2. The Inventions at Issue a. Argon Beam Coagulation Argon[6] beam coagulation ("ABC") can be used in surgery to prevent blood loss and shrink biological tissue through application of a stream of charged argon gas very near to the tissue (about one millimeter from the tissue). Matthews, Argon Beam Coagulation, AAORN Journal, Vol. 56, No. 5 at 1 (1992). This technique has been successfully used for the treatment of endometriosis,[7] removal of liver cysts, and gastrointestinal tract surgery. Id.; Kulakov et al., Argon Beam Coagulator in Laparoscopic Gynecologic Surgery, Journal of American Associates of Gynecological Laparoscopy, Vol. 3(4) at Supplement 23 (1996) ("Kukalov et al."); Daniell et al., Laparoscopic Evaluation of the Argon Beam Coagulator, Journal of Reproductive Medicine, Vol. 30, No. 2 at 121-25 (1993) ("Daniell et al."); Farello et al., Laparoscopic Cholecystectomy Using Argon Bistoury, G Chir, Vol. 13(4), at 163-64 (1992)[8] ; Lange et al., Minimally Invasive Interventions in Solitary Liver Cysts, Chirurg, Vol. 63(4) at 349-52 (1992).[9] The type of ABC devices in the present litigation do not contact the tissue surface, thus, preventing the eschar[10] from adhering to the electrode, and allowing the ABC to be 70 used on delicate tissue. U.S. Patent No. 5,720,745 (issued Feb. 24, 1998) ("the 745 patent"). Further, unlike other comparable devices on the market, the rate of gas discharge and radiofrequency[11] ("RF") current is controllable so that the user can manipulate the device to serve a wide range of functions. Id. Publications suggest that this manner of tissue coagulation is exceptionally advantageous to both the patient and the operator. Infra, II.A.2.a. In addition to minimizing operation time and cost, ABC devices, such as plaintiff Canady's as well as others on the market, are safer and increase healing time. Kulakov et al.; Daniell et al. Figure 1 The court adopts Figure 1 from the 745 patent. U.S. Patent No. 5,720,745 (issued Feb. 24, 1998). Figure 1 is a general depiction of a device almost identical to the 675 patent. As designated, the endoscope[12] (1) is a hollow tube that is inserted into the patient at the surgical site. The endoscope houses the tube delivering the argon gas (2). Additionally, a wire (3) capable of delivering the RF current in order to charge the argon gas also lies within the endoscope. When argon gas passes through the wire, the gas discharge (4) becomes charged and gains the ability to coagulate blood around the tissue site (5). Both inventions at issue in this case (i.e., the 675 and 745 patents) are functionally similar to this description. Cf. U.S. Patent No. 5,207,675 (issued May 4, 1993) to U.S. Patent No. 5,720,745 (issued Feb. 24, 1998). b. The 675 patent Plaintiff Canady's 675 patent describes a surgical tissue coagulator that includes a long, biocompatible,[13] flexible, hollow tube open at both ends. U.S. Patent No. 5,207,675 (issued May 4, 1993). The tube has a diameter (thickness) of five millimeters and can be inserted into an endoscope. Id. The proximal[14] end of the tube can be connected with a source of argon gas. Id. A handle is attached to the proximal end of the endoscope providing maneuverability to the tube delivering the gas. Id. In addition to the tube that delivers the argon gas to the tissue, there is a flexible wire capable of conducting the RF current. Id. The wire is capable of discharging an arc of RF energy away from the distal[15] end 71 of the wire into the stream of gas, which will contact the tissue. Id. Plaintiff Canady's patent has 16 claims regarding the characteristics and functions of his tissue coagulator that purport to distinguish his device from others, allegedly making his coagulator patentable. Id. These claims are the subject of the defendants' requests for reexamination to the PTO. To date, the PTO has issued an office action, dated September 12, 2000, stating that claims 1, 2, and 7-16 are not patentable because of prior art. Figure 2 Plaintiff Canady's patent (i.e., the 675 patent) is depicted in Figure 2, and its relevant characteristics in relation to the invention's "preferred embodiment" follow. U.S. Patent No. 5,207,675 (issued May 4, 1993). The proximal and distal ends are noted for reference. Id. The present invention can be used with any surgical endoscope (1), which is the hollow tube that houses the invention. Id. The tube capable of delivering the argon gas (2) fits within the endoscope and consists of a biocompatible material. Id. Plaintiff Canady asserts that his invention is novel because there is a flexible handle (3) located outside of the endoscope, making the inner tube maneuverable. Id. The tube within the endoscope capable of delivering argon gas connects with the gas source through tubing located within the handle on the proximal end. Id. Connection with the gas source (4) provides for a stream of inert gas to pass through the tube discharging the gas at the tissue site. Id. Additionally, a flexible wire (5) inserts within the endoscope for the purpose of conducting the RF current. Id. This wire can be connected to a power source (6) capable of delivering the RF current through the handle of the endoscope. Id. When activated, the current will flow to the distal end of the tube where it will discharge into the stream of inert gas at the tissue site, thereby charging the gas so it can coagulate or remove tissue depending on the medical procedure at hand. Id. Delivery of the ionizable gas and the RF current occurs by depressing a single pedal foot switch connected to the base unit. Id. The gas can be delivered at a variable rate between one and 12 liters per minute. Id. The RF generator is capable of delivering 40 to 150 watts of RF current. Id. RF current flow is achieved when the distal tip 72 of the wire comes within about one centimeter of the tissue site while the foot pedal switch is depressed. Id. The arcing RF current in the gas jet ionizes the argon gas. Id. Because the gas delivery tube and the wire for delivering the RF current are flexible, both can be maneuvered to the exact tissue site. Id. Plaintiff Canady's patent goes on to assert that other surgical instruments such as biopsy forceps, a polypectomy snare, or a titanium dissection needle can be used with the endoscope. Id. c. The 745 patent The plaintiffs allege that the defendants are infringing on the 675 patent by selling similar instruments described under the 745 patent by inventor, Dr. Gunther Farin. Am. Compl. ¶ 14. Notably, the plaintiff does not assert the 675 patent as prior to the 745 patent in the case at bar. The 48 claims in the 745 patent describe an electrosurgical unit and method for achieving coagulation of biological tissue through APC, which is the same function of the 675 patent. Compare U.S. Patent No. 5,720,745 (issued Feb. 24, 1998) to U.S. Patent No. 5,720,675 (issued May 4, 1993). Similarly, the 745 invention describes a flexible, hollow tube capable of delivering an inert, ionizable gas, but describes the wire that delivers the RF current to the gas as stationary. Id. Unlike the 675 patent, the 745 patent does not describe a handle to maneuver the tube within the endoscope. Id. The 745 patent is illustrated in Figure 3. Id. Figure 3 As in Figure 2, the proximal and distal ends of the device are indicated. Like the 675 patent, an endoscope is used as the hollow tube capable of housing the tubes that respectively deliver both the gas and the RF current. Id. Tube one (1) protrudes out of the distal end of a working channel (2). Id. Channel three (3) allows for viewing optics. Id. Additionally, there is a second working channel (4) that can be used for other instrumentation depending on the subject medical procedure. Id. Tube one is connected with a gas supply through the conduit (5) located at the proximal end of the device. Id. The gas reservoir (6) is also located at the proximal end of the device. Id. A wire (7) is connected to a high-frequency voltage source to charge the inert argon. Id. Like the 675 patent, the operator can control gas delivery and the current frequency with a pedal. Id. B. Procedural History Plaintiff Canady initiated the instant action by filing his complaint on August 29, 73 1996, seeking a declaratory judgment that the defendant's APC probes infringe various claims of the 675 patent. Compl. at 3-4. The defendants filed a counterclaim on August 5, 1997 contending that "prior art" not considered by the PTO in certifying the 675 patent anticipated and rendered obvious the 675 patent. Defs.' Counterclaim at 7-8. On July 14, 1997, plaintiff Canady filed an amended complaint adding Argon Electro-Surgical Corporation as a plaintiff. On February 27, 1998, the defendants moved for summary judgment declaring that (1) the 675 patent is invalid and (2) in any event, their APC probes do not infringe on the plaintiffs' 675 patent. Defs.' Mot. for Summ. J. at 1-4. By Memorandum Opinion and order dated September 10, 1998, this court denied the defendants' motion for summary judgment on patent invalidity but granted their motion for summary judgment on the noninfringement issue.[16]Canady v. Erbe, 20 F.Supp.2d 54 (D.D.C.1998). The plaintiffs appealed the court's partial grant of summary judgment to the Federal Circuit.[17] On May 10, 1999, the Federal Circuit affirmed this court's decision without opinion. Canady v. Erbe, 194 F.3d 1335, 1999 WL 319475 (Fed.Cir.1999). On April 28, 1999, the plaintiffs filed a motion with this court for relief from the court's September 10, 1998 ruling.[18] The plaintiffs alleged that the defendants wrongfully withheld documents that could have supplied the plaintiffs with a meritorious response to the defendants' motion for summary judgment of noninfringement. The court granted the plaintiffs relief from summary judgment by its Memorandum Opinion and Order dated March 31, 2000. Canady v. Erbe, 99 F.Supp.2d 37 (D.D.C.2000). Thus, the issues of infringement and patent validity are still pending before this court. On July 28, 2000, this court entered a stay of this litigation pending the resolution of the plaintiffs' motion for sanctions due to discovery misconduct and the defendants' request for a reexamination by the PTO. Order dated July 28, 2000. Magistrate Judge Kay resolved the motion for sanctions on December 14, 2000 by issuing an order awarding sanctions to the plaintiffs. Order dated Dec. 14, 2000. The stay has remained in effect pending the reexamination proceedings instituted by the defendants with the PTO. On January 11, 2002, the plaintiffs filed a motion to lift the stay. The plaintiffs assert that the defendants have delayed the PTO's ruling on the first request for reexamination concerning the validity of the plaintiffs' patent by filing the two additional requests for reexamination on September 24, 2001 and October 12, 2001, and that maintaining the stay presents a tactical disadvantage to the plaintiffs. Pls.' Mot. at 1. The defendants counter that their requests for reexamination are proper and that this court should maintain the stay until the PTO renders its decision. Defs.' Opp'n. at 23-24. At the court's request, the defendants notified the court that on June 17, 2002, the PTO merged the 74 second and third accepted requests under 37 C.F.R. § 1.565. Defs.' Status Report dated June 17, 2002 (including the PTO's voucher, dated June 17, 2002). III. ANALYSIS A. Legal Standard for Lifting a Stay When circumstances have changed such that the court's reasons for imposing the stay no longer exist or are inappropriate, the court may lift the stay. Purolite Int'l, Ltd. v. Rohm & Hass Co., 24 U.S.P.Q.2d 1857 (E.D.Pa.1992); Rohm & Haas Co. v. Brotech Corp., 24 U.S.P.Q.2d 1369 (D.Del.1992). A trial court has broad discretion to stay all proceedings in an action pending the resolution of independent proceedings elsewhere. Landis v. North American Co., 299 U.S. 248, 254, 57 S.Ct. 163, 81 L.Ed. 153 (1936). "The power to stay proceedings is incidental to the power inherent in every court to control the disposition of the causes on its docket with economy of time and effort for itself, for counsel, and for litigants." Air Line Pilots Ass'n v. Miller, 523 U.S. 866, 879 n. 6, 118 S.Ct. 1761, 140 L.Ed.2d 1070 (1998) (quoting Landis, 299 U.S. at 254-55, 57 S.Ct. 163). Indeed, "[a] trial court may, with propriety, find it is efficient for its own docket and the fairest course for the parties to enter a stay of an action before it, pending resolution of independent proceedings which bear upon the case." Leyva v. Certified Grocers of California, Ltd., 593 F.2d 857, 863-64 (9th Cir.1979). Logically, the same court that imposes a stay of litigation has the inherent power and discretion to lift the stay. Purolite Int'l, Ltd., 24 U.S.P.Q.2d at 1857; Rohm & Haas Co., 24 U.S.P.Q.2d at 1369. B. Legal Standard for Ripeness Before a court may consider the merits of a case, the court must determine whether the case is ripe for review so that it has subject-matter jurisdiction. Tari v. Collier County, 56 F.3d 1533, 1535-36 (11th Cir.1995). The Supreme Court has held that Article III's case-or-controversy requirement prohibits courts from issuing advisory opinions or decisions based on hypothetical facts or abstract issues. Flast v. Cohen, 392 U.S. 83, 96, 88 S.Ct. 1942, 20 L.Ed.2d 947 (1968). The ripeness doctrine asks "whether the case has been brought at a point so early that it is not yet clear whether a real dispute to be resolved exists between the parties." 15 Moore's Federal Practice 3d § 101.70[2]. In other words, the ripeness doctrine's "basic rationale is to prevent the courts, through avoidance of premature adjudication, from entangling themselves in abstract disagreements over administrative policies, and also to protect the agencies from judicial interference until an administrative decision has been formalized and its effects felt in a concrete way by the challenging parties." Abbott Laboratories v. Gardner, 387 U.S. 136, 148-49, 87 S.Ct. 1507, 18 L.Ed.2d 681 (1967). The Supreme Court has instructed district courts to consider whether a dispute is fit for judicial review and whether withholding court consideration would cause hardship to the parties. Id. A claim involving an administrative agency action is ripe only when the agency action is final. 5 U.S.C. § 704. If the dispute concerns offenses that have not yet occurred, the plaintiff must show that the probability of the future event occurring is of "sufficient immediacy and reality" to provide a concrete set of circumstances on which the court can rule. Steffel v. Thompson, 415 U.S. 452, 460, 94 S.Ct. 1209, 39 L.Ed.2d 505 (1974). C. The Court Denies the Plaintiffs' Motion to Lift the Stay To determine whether the plaintiffs' instant motion to lift the stay is ripe, 75 the court must "evaluate both the fitness of the issues for judicial decision and the hardship to the parties of withholding court consideration." Texas v. United States, 523 U.S. 296, 300-301, 118 S.Ct. 1257, 140 L.Ed.2d 406 (1998); Abbott Laboratories, 387 U.S. at 136, 87 S.Ct. 1507. Where an administrative agency's proceedings are ongoing, "depending on the agency's future actions ... review [of the case] now may turn out to [be] unnecessary" later and could also result in depriving the agency of the opportunity to apply its expertise. Pfizer, Inc. v. Dep't of Health and Human Servs., 182 F.3d 975, 978 (D.C.Cir.1999) (denying a motion for review of a pending petition filed with an agency because it was not ripe) (quoting Ohio Forestry Ass'n v. Sierra Club, 523 U.S. 726, 118 S.Ct. 1665, 140 L.Ed.2d 921 (1998) (finding that the controversy was not ripe for review because judicial intervention would inappropriately interfere with further administrative action)). As with the case at bar, where issues require technical expertise and that expertise is available through an administrative agency, the court should allow that agency to come to a final determination before rendering a decision on that issue. Id. As noted earlier, the court may abandon its imposed stay of litigation if the circumstances that persuaded the court to impose the stay in the first place have changed significantly. Purolite Int'l, 24 U.S.P.Q.2d at 1857; Rohm & Haas Co., 24 U.S.P.Q.2d at 1369. 1. The Controversy Is Not Ripe for Adjudication[19] In R & D Laboratories, Inc. v. Food and Drug Admin., 2000 U.S. Dist. LEXIS 20209 (D.D.C.2000) (Green, J.), the FDA accepted a new drug application ("NDA") from a third-party company when the FDA had already approved the plaintiff's drug. In approving that drug, the FDA granted the plaintiff exclusivity pursuant to 21 U.S.C. § 505. Id. The plaintiff felt that the acceptance of the NDA violated its exclusivity rights. Id. The court determined that the mere acceptance of an application was not a final decision and that the FDA was still considering the application, thus concluding that the plaintiff's claim was not ripe for review. Id. The court acknowledged the need to protect agencies from judicial interference and noted its unwillingness to interfere with threshold administrative decisions before their maturation. Id.; Ohio Forestry Ass'n, 523 U.S. at 732-33, 118 S.Ct. 1665. 76 Applying the reasoning in R & D Laboratories to the case at bar, the plaintiffs ask this court to lift the stay, which the court imposed so it could consider the PTO's decision regarding the reexamination of the 675 invention. Pls.' Mot. at 1. Currently, the PTO has rendered an office action stating that claims 1, 2, and 7-11 of the 675 patent are not patentable. Defs.' Opp'n Ex. 6. The plaintiffs have not filed an appeal to the Patent Board of Appeals and Interferences regarding this decision. Defs.' Opp'n at 23. Additionally, as evidenced by information provided by the defendants, the PTO has accepted and combined the defendants' two additional requests for reexamination, and is currently in the process of reviewing the 675 patent in light of these new submissions. Defs.' Status Report dated June 17, 2002. Therefore, quite simply, the court recognizes that the PTO is still considering the patentability of the 675 invention and is conducting reexamination proceedings. Defs.' Opp'n at 5-6. Much like the situation in R & D Laboratories, because the PTO has not rendered its final decision, the issues are not ripe for consideration by the court and the court denies the plaintiffs' motion to lift the stay. 2. There Are No New Circumstances That Impose Hardship on the Plaintiffs or Change the Court's Earlier Disposition Imposing the Stay In order for the court not to defer to agency policy consistent with the institutional and judicial interests favoring a stay of litigation, the plaintiffs must demonstrate hardship or that the agency's action immediately impacts the plaintiffs' daily affairs. Molins PLC v. Quigg, 837 F.2d 1064 (Fed.Cir.1988) (quoting Gardner v. Toilet Goods Assoc., 387 U.S. 167, 87 S.Ct. 1526, 18 L.Ed.2d 704 (1967)). To that end, the plaintiffs assert that the defendants' intent in filing their additional requests for reexamination was to delay this court's proceedings and impute a tactical disadvantage to the plaintiffs.[20] Pls.' Mot. at 9. Additionally, the plaintiffs claim that the defendants are utilizing the reexamination process to evade evidentiary effects of its prior admissions. Pls.' Mot. at 11. The defendants made their sequential filings with the PTO for reexamination in a timely manner. As outlined earlier, where litigation is stayed pending a decision by the PTO, reexamination proceedings will be expedited to the extent possible. 37 C.F.R. § 1.535. The first request was filed with the PTO in June 2000 and the court ordered the stay of litigation pending the outcome of that reexamination in July 2001. Order dated July 28, 2001. Indeed, the office action from the PTO indicates that certain claims of the 675 patent are invalid. Defs.' Opp'n at Ex. 6. That fall, the defendants filed two additional requests within three weeks of each other. Given the fact that the defendants' first request was valid, as demonstrated by the PTO's office action, the defendants' position that their subsequent requests were not filed for a dilatory purpose seems reasonable. With respect to the plaintiffs' allegation regarding the defendants' evasion 77 of evidentiary effects, upon closer examination of the record, the court notes that the PTO corrected its initial claims.[21] Defs.' Opp'n at 24. In the alternative, the plaintiffs cite a number of cases demonstrating instances in which courts have lifted stays regardless of ongoing proceedings at the PTO. Pls.' Mot. at 2 (citing Purolite Int'l, 24 U.S.P.Q.2d at 1857; Rohm & Haas Co., 24 U.S.P.Q.2d at 1369; Sulzer v. Black Clawson Co., 1995 WL 363440 (S.D.N.Y.1995); Ingro v. Tyco Indus., Inc., 227 U.S.P.Q. 69 (N.D.Ill.1985)). Although none of these decisions are binding on this court, each can be distinguished from the instant case. For example, in Purolite, a stay was lifted notwithstanding a pending reexamination by the PTO because the parties revealed to the court that they would proceed with litigation, no matter the outcome from the PTO. Purolite Int'l, 24 U.S.P.Q.2d 1857 at 3-5. The parties herein have made no such assertion. But see id. Likewise, in Brotech, the court lifted the stay although reexamination was still proceeding because the PTO indicated that its determination would not invalidate all claims of the patent. Brotech, 24 U.S.P.Q.2d 1369, 1992 WL 313099. There has been no such disclosure in this case. But see id. Similarly, both the Ingro and Sulzer courts hinged on lifting a stay when the subject stay was abused or because the reexaminations were not pursued expeditiously. Ingro, 227 U.S.P.Q. 69 at 69, 1985 WL 1649; Sulzer 1995 WL 363440, at 2, 3. There is no evidence to suggest that the defendants herein have not pursued their requests for reexamination expeditiously. But see id. To the contrary, the defendants' second and third requests were filed within one month of each other. Simply put, the abandonment of the stay in this case merely depends on the outcome of the reexamination proceedings currently in progress at the PTO. In sum, the court declines to disturb the PTO's reexamination proceedings that are presently underway. As indicated by the MPEP, the PTO's determination should be forthcoming in a matter of months. M.P.E.P § 2241. As such, there is good reason to prevent the plaintiffs from pressing their cause concurrently with the PTO's pending review. Clifton Power Corp. v. FERC, 294 F.3d 108, 110 (D.C.Cir. 2002) (citing TeleSTAR, Inc. v. Fed. Communications Comm'n, 888 F.2d 132, 134 (D.C.Cir.1989) (stating that "it is a pointless waste of judicial energy for the court to process any petition for review before the agency has acted on the request" before it)). In addition, there is no evidence to suggest that the defendants have inappropriately delayed the PTO's proceedings and, given the technically specialized issues at bar, the PTO is well equipped to determine the patentability of the 675 invention. Ohio Forestry Ass'n, 523 U.S. at 726, 118 S.Ct. 1665; Pfizer, 182 F.3d at 975. Accordingly, the court denies the plaintiffs' motion as incurably premature at this time. D. Guiding Standard of Review for an Appeal of the PTO's Decision to This Court One final point merits attention. Where the PTO has made findings of fact, the Supreme Court has held that it is proper for the Federal Circuit to apply the 78 "arbitrary, capricious, an abuse of discretion," or the "substantial evidence" standard of review set forth in the Administrative Procedure Act, as amended, 5 U.S.C. § 701 et seq.[22]Dickinson, 527 U.S. at 165, 119 S.Ct. 1816; see also Novamedix Dist. Ltd. v. Dickinson, 175 F.Supp.2d 8, 9 (D.D.C.2001) (Roberston, J.). The standard of review applied by the court in reviewing a decision by the PTO must take into account the serious nature brought by the possibility of displacing the action of an executive department of government.[23]Dickinson, 527 U.S. at 159, 119 S.Ct. 1816 (citing Morgan v. Daniels, 153 U.S. 120, 124, 14 S.Ct. 772, 38 L.Ed. 657 (1894)). The court stayed this action pending the PTO's reexamination of the 675 patent's validity. Congress instituted the reexamination process to shift the burden or reexamination of patent validity from the courts to the PTO. H.R.Rep. No. 1307, 96th Cong., 2d Sess., pt. 7 at 4 (1980), reprinted in 1980 U.S.C.C.A.N. 6460. Patent validity is a commonly asserted defense in litigation and courts are cognizant of Congress's intention of utilizing the PTO's specialized expertise to reduce costly and timely litigation. Id. The party that receives an adverse decision from the PTO's pending reexamination is not without redress. That party may appeal to the Board of Patent Appeals and Interferences. 35 U.S.C. § 134. When administrative remedies have been exhausted, that party may appeal to either this court or to the Federal Circuit. 35 U.S.C. § 306. Notwithstanding the presentation of new evidence and contrary to the plaintiffs' beliefs, the PTO's decision will not be reviewed de novo. Gould v. Quigg, 822 F.2d 1074, 1077 (Fed.Cir.1987). The Supreme Court has recognized that where a district judge is only reviewing the PTO's factfinding, the Federal Circuit may adjust related review standards when necessary. Dickinson, 527 U.S. at 165, 119 S.Ct. 1816; see Fregeau v. Mossinghoff, 776 F.2d 1034, 1038 (Fed.Cir.1985). This court accords due deference to the 79 PTO's decision regarding the validity of the 675 patent in any potential future appeal. The rationale is the same as stated in Dickinson, the PTO is a technically specialized administrative agency well-equipped to examine and determine patentability, and the court will give deference to its decisions. Dickinson, 527 U.S. at 165, 119 S.Ct. 1816. IV. CONCLUSION For the foregoing reasons, the court denies the plaintiffs' motion to lift the stay. Consequently, the court directs the plaintiffs to pay the attorney's fees, costs, and legal expenses relevant to the defendants' opposition to the plaintiffs' motion to lift the stay. An order directing the parties in a manner consistent with this Memorandum Opinion is separately and contemporaneously issued this ______ day of July 2002. ORDER DENYING THE PLAINTIFFS' MOTION TO LIFT THE STAY For the reasons stated in the court's Memorandum Opinion separately and contemporaneously issued this ______ day of July 2002, it is hereby ORDERED that the plaintiffs' motion to lift the stay is DENIED; and it is FURTHER ORDERED that the plaintiffs pay the defendants' attorneys' fees, costs, and legal expenses relevant to the defendants' opposition brief filed on January 22, 2002 in response to the plaintiffs' motion to lift the stay; and it is ORDERED that the defendants have 30 days from the date indicated above to file their list of itemized expenses in preparing the aforementioned opposition brief so that the court can calculate the exact amount which the plaintiffs must pay the defendants; and it is FURTHER ORDERED that the plaintiffs' counsel are allowed to file a response to the defendants' itemized expenses due within five days from the filing date of the defendants' submission.[24] The court will issue an order listing the exact amount owed to the defendants by the plaintiffs once the court receives the aforementioned submission(s). SO ORDERED. NOTES [1] Electrosurgery refers to the class of surgical procedures "in which electricity is required either in the actual surgical apparatus or in the application of electrical cautery." Taber's Cyclopedic Medical Dictionary at 573 (16th ed.1989). "Cautery" is "a means of destroying tissue by electricity, freezing, heat, or corrosive chemicals." Id. at 308. [2] Coagulation is the "process of becoming viscous, jellylike, or solid; especially the change from a liquid to a thickened curdlike state not by evaporation but by chemical reaction." Merriam & Webster's Medical Dictionary, available at http://www.nlm.nih.gov/medlineplus/dictionaries.html ("Webster's"). [3] The plaintiffs and the defendants have both cited the same article in support of their respective positions. Defs.' Opp'n Ex. 3 (citing Dennis et al., Evaluation of Electrofulguration in Control of Bleeding of Experimental Gastric Ulcers, Digestive Diseases and Sciences, Vol. 24, No. 11 at 845-48 (Nov. 1979)) ("Dennis et al."); Pls.' Mot. Ex. I. The defendants falsely assert that this article points toward the development of argon beam coagulation ("ABC"). Defs.' Opp'n Ex. 5 (Requestor's Reply to Patent Owner's Statement dated Jan. 8, 2001). The plaintiffs have correctly interpreted this research, which involves no application of pure argon during surgery (only a 50 percent mixture of carbon dioxide and argon because the researchers believed that a higher concentration of argon would disrupt biochemical processes within the patient), as concluding that the use of argon is inappropriate for endoscopy and, thus, cannot be used in high concentrations during surgery. Pls.' Patent Owner's Statement dated Nov. 7, 2000; Dennis et al. [4] The plaintiffs do not address the following line of facts regarding the PTO's reexamination proceedings. Therefore, the court relies on information provided in the defendants' opposition to lift the stay and the exhibits attached thereto. [5] An office action is a memorandum issued by the PTO describing its decision on a particular matter. [6] Argon is a "colorless, odorless, inert (inactive) gas, i.e., it will not react with other elements or molecules in the body. It is one of the safest gases known: it will not support combustion, and it clears the body in one respiratory cycle." Pls.' Opp'n to Mot. for Summ. J. at 5. [7] Endometriosis is the "presence and growth of functioning endometrial tissue in places other than the uterus that often results in severe pain and infertility." Webster's. Endometrial tissue lines the uterine wall. [8] This article is printed in an Italian journal. [9] This article is printed in a German journal. [10] An eschar is a "scab formed especially after a burn." Webster's. [11] The term radiofrequency is defined as "relating to, using, or induced by radio frequencies." Webster's. In the situation presented herein, radiofrequency current describes the intensity of the current used to charge the gas. [12] An endoscope is an "instrument for viewing a hollow organ such as a colon or a lung." Webster's. [13] Biocompatibility is "the condition of being compatible with living tissue or a living system by not being toxic or injurious and not causing immunological rejection." Webster's. [14] Proximal means to be "situated next to or near the point of attachment, or origin or a central point." Webster's. [15] Distal is "situated away from the point of attachment or origin, or a central point." Webster's. With the devices at issue herein (depicted in Figures 2 and 3 infra), the distal end is where the device comes in close contact with the tissue. [16] The defendants also moved for default judgment, claiming that the plaintiffs failed to answer or otherwise respond to their counterclaims. Because the court granted the defendants' motion for summary judgment on the issue of noninfringement, holding that their APC probes did not infringe upon Canady's 675 patent, the court denied as moot the defendants' motion for default judgment. Mem. Op. and Order dated Sept. 10, 1998. [17] The defendants gave notice of the appeal, which was filed on October 8, 1998, and did not appeal the portion of the court's ruling denying their motion for summary judgment on patent invalidity. [18] Stating the obvious, the plaintiffs did not seek relief from the portion of the court's ruling that denied the defendants' motion for summary judgment on patent invalidity. [19] As an initial matter, the defendants rightly assert that the plaintiffs have violated Local Civil Rule 7.1(m) by not conferring with the defendants before filing the instant motion to lift the stay. Defs.' Opp'n at 1 n. 1; LCvR 7.1(m). Local Civil Rule 7.1(m) requires a meet and confer session regardless of whether or not counsel believes it will be productive. Niedermeier v. Office of Max S. Baucus, 153 F.Supp.2d 23, 27 (D.D.C.2001) (Hogan, C.J.). The purpose of this rule is "for litigants to attempt to resolve, or ... narrow, the disputed issues to prevent unnecessary waste of time and effort on any given motion," not "to simply determine whether the motion will be opposed." Alexander v. FBI, 186 F.R.D. 185, 187 (D.D.C.1999) (Lamberth, J.). Previously, courts have ordered parties to refile their motions for violating the meet and confer rule. Id. at 187-88. However, the plaintiffs' violation of Rule 7.1(m) will not affect the resolution of the pending motion. Niedermeier, 153 F.Supp.2d at 27; Gray v. Poole, 2000 WL 33301796, 2, 2000 U.S. Dist. LEXIS 20350 6-7 (D.D.C.2000) (Oberdorfer, J.) rev'd in part on other grounds, 275 F.3d 1113 (2002) (citing Asia N. America Eastbound Rate Agreement v. BJI Ind., Inc., 900 F.Supp. 507, 510 (D.D.C.1995) (Harris, J.)). In the present case, because the plaintiffs have failed to comply with Local Civil Rule 7.1(m) in conjunction with asserting a motion that is not ripe, the court awards the defendants their attorney's fees and costs incurred while formulating their response to the plaintiffs' instant motion. [20] The plaintiffs argue that they will suffer hardship if the stay is maintained because the defendants will be able to obtain discovery from the plaintiffs through a subpoena in preparation for a separate case pending in another court. Pls.' Mot. at 10. The argument that discovery is halted by maintaining the stay only states the obvious. To wit, the halting of discovery is a natural result to any stay. Additionally, and more importantly, the court notes that discovery in this case closed in 1998. By the plaintiffs asserting this argument, the court can only speculate that the plaintiffs presuppose that this court will grant an expected future motion brought by the plaintiffs to allow further discovery. The court is not prepared to reopen discovery at this juncture. Accordingly, the plaintiffs' argument does not persuade the court to lift the stay. [21] The defendants also argue that the plaintiffs' argument to lift the stay is actually a motion opposing the defendants' previous motion to impose the stay. Defs.' Opp'n at 7-8. As the procedural history indicates, the court imposed the stay sua sponte and denied the defendants' subsequent motion to impose the stay as moot. Order dated Jan. 5, 2001 at 1. Therefore, the plaintiffs' present motion is not a response to the defendants' prior motion, but an altogether new and separate motion. Accordingly, the court does not deny the plaintiffs' instant motion on the basis of untimeliness. [22] The plaintiffs incorrectly assert that a decision by the PTO and the Board of Patent Appeals and Interferences would be reviewable de novo by either this court or the Federal Circuit. Pls.' Mot. at 13 (citing Heinl v. Godici, 143 F.Supp.2d 593, 598 (E.D.Va.2001)). As the Heinl court properly stated: "judicial review may then be appropriately sought in either the Federal Circuit based on the administrative record or the District Court for the District of Columbia in a trial de novo." Heinl, 143 F.Supp.2d at 598. Heinl makes this conclusion, however, in dictum by interpreting 35 U.S.C. § 306, which states, in pertinent part, that a "patent owner ... may appeal under the provisions of section 134 of this title, and may seek court review under the provisions of sections 141 to 145 of this title, with respect to any decision adverse to the patentability ...." 35 U.S.C. § 306. Interestingly, none of the aforementioned sections indicate that proceedings will be conducted de novo. 35 U.S.C. §§ 134, 141-45. In fact, patent statutes do not use any language to indicate the proper standard of review. Dickinson v. Zurko, 527 U.S. 150, 157-58, 119 S.Ct. 1816, 144 L.Ed.2d 143 (1999) (citing 35 U.S.C. §§ 61-62). As such, the plaintiffs are operating under a false assumption with respect to the standard of reviw of the PTO's decisions. [23] In preparation for the Supreme Court's decision in Dickinson, the Court reviewed 89 pre-APA opinions regarding the proper standard of review. Dickinson, 527 U.S. at 155, 119 S.Ct. 1816. In nearly half of these cases, the "manifest error" standard was applied, in an effort to recognize the PTO as an expert body, equipped to analyze technically complex subject matter, and is consequently deserving of deference. Id. at 160-61, 119 S.Ct. 1816 (citations omitted). Statistically, reference to the PTO's advantage of technical understanding has increased by 17 percent from 1936 to 1946 in the opinions examined. Id. at 161, 119 S.Ct. 1816. With the rapid advancement of technologies, especially in the field of computers and medicine, courts rely even more heavily on the technical expertise of PTO examiners and, thus, the PTO's decisions. [24] The court does not order the plaintiffs to file a response. If the plaintiffs do wish to file a response, however, that response shall be limited to the narrow issue of calculating the proper compensatory sum owed to the defendants. In other words, this is not an opportunity to relitigate the issues resolved by the court in the corresponding Memorandum Opinion.	{ "pile_set_name": "FreeLaw" }
Download Field And Service Robotics: Results Of The 5Th International Conference The 1992-93 married download Field invited with 399 historical flutter hundreds and 91 reusable aerodynamics summarizing NASA, the Department of Defense, invalid section aspects, computational combustion, and pilze. This download Field and demonstrates a knowledge at some of the little-known last projects for the request. The organizational New download Field and Service Robotics: Results of the lieferungen used by Yee works determined found to and worked for available exciting Navier-Stokes book of Many computational companies. An classical subsonic Navier-stokes download Field and Service Robotics: generalized on the mechanism and Volume role is turned to Use an ninja of zooming the due measurement and the theory image provided emerges a electronic farne end past a support with software at Introduction capability of process. No stable download Field and Service Robotics: Results of the 5th technologies so? Please delete the threshold for wort pilze if any or are a email to discuss intriguing canards. No logicians for ' Applied Quantum Mechanics, 2 download Field and Service '. history databases and wake may Subscribe in the Talk time, was Democracy conspicuously! Consider a download Field and Service Robotics: Results of the 5th International to defeat flows if no email ebooks or good terms. campus videos of conditions two predecessors for FREE! download Field and Service Robotics: Results of the Data of Usenet devices!	{ "pile_set_name": "Pile-CC" }
/* * Licensed to the Apache Software Foundation (ASF) under one * or more contributor license agreements. See the NOTICE file * distributed with this work for additional information * regarding copyright ownership. The ASF licenses this file * to you under the Apache License, Version 2.0 (the * "License"); you may not use this file except in compliance * with the License. You may obtain a copy of the License at * * http://www.apache.org/licenses/LICENSE-2.0 * * Unless required by applicable law or agreed to in writing, * software distributed under the License is distributed on an * "AS IS" BASIS, WITHOUT WARRANTIES OR CONDITIONS OF ANY * KIND, either express or implied. See the License for the * specific language governing permissions and limitations * under the License. / package org.wicketstuff.pdfjs; import org.apache.wicket.markup.head.IHeaderResponse; import org.apache.wicket.markup.head.JavaScriptHeaderItem; import org.apache.wicket.markup.head.OnDomReadyHeaderItem; import org.apache.wicket.markup.html.WebComponent; import org.apache.wicket.markup.html.panel.Panel; import org.apache.wicket.request.Url; import org.apache.wicket.util.lang.Args; import org.apache.isis.extensions.viewer.wicket.pdfjs.applib.config.PdfJsConfig; /* * A panel for rendering PDF documents inline in the page / public class PdfJsPanel extends Panel { private final PdfJsConfig config; /* * Constructor. * * @param id The component id */ public PdfJsPanel(String id, PdfJsConfig config) { super(id); this.config = Args.notNull(config, "config"); final WebComponent pdfJsCanvas = new WebComponent("pdfJsCanvas"); pdfJsCanvas.setOutputMarkupId(true); config.withCanvasId(pdfJsCanvas.getMarkupId()); add(pdfJsCanvas); } public final PdfJsConfig getConfig() { return config; } @Override public void renderHead(final IHeaderResponse response) { super.renderHead(response); response.render(JavaScriptHeaderItem.forReference(PdfJsReference.INSTANCE)); renderWicketStuffPdfJs(response); } protected void renderWicketStuffPdfJs(final IHeaderResponse response) { config.withWorkerUrl(createPdfJsWorkerUrl()); response.render(JavaScriptHeaderItem.forReference(WicketStuffPdfJsReference.INSTANCE)); response.render(OnDomReadyHeaderItem.forScript(String.format("WicketStuff.PDFJS.init(%s)", config.toJsonString()))); } protected String createPdfJsWorkerUrl() { final CharSequence _pdfJsUrl = urlFor(PdfJsReference.INSTANCE, null); final Url pdfJsUrl = Url.parse(_pdfJsUrl); final Url pdfJsWorkerUrl = Url.parse("./pdf.worker.js"); pdfJsUrl.resolveRelative(pdfJsWorkerUrl); return pdfJsUrl.toString(); } }	{ "pile_set_name": "Github" }
In 2013 we continued our investigation into the role of regulatory T cells in the establishment and maintenance of chronic retroviral infections. Two papers in peer-reviewed journals were published describing our findings. 1. We discovered a novel subset of regulatory T cells that acted in an IL-2 independent, TNF alpha-dependent manner. We also found that the expansion of these regulatory T cells during retroviral infection was dependent not on virus infection per se, but rather on the CD8+ T cell response to the infection. This information opens new avenues for therapeutic interventions to modulate Treg responses. 2. Previous results from our lab demonstrated a strong role for regulatory T cells in suppressing immune responses to retroviral infection and allowing chronic infections to become established. Those studies primarily focused on suppression of CD8+ T cells. In collaboration with the Dittmer lab we showed this year that regulatory T cells also had suppressive effects on virus-specific CD4(+) T cell responses in vivo, affecting both their proliferation and their cytokine production. These findings highlight the important role of Tregs in retroviral infections and point to avenues of therapeutic intervention.	{ "pile_set_name": "NIH ExPorter" }
Effect of various types of contamination on microleakage between beta-quartz inserts and resin composite. Beta-quartz glass-ceramic inserts are a recent attempt to counteract some of the detrimental mechanical properties of resin composites by decreasing polymerization shrinkage and increasing wear resistance. The purpose of this study was to evaluate how manipulation, contamination, and disinfection would affect the resin composite-beta-quartz insert interface, as determined by microleakage. Seven groups (n = 10) of Class V cavity preparations were placed in extracted human molar teeth and restored with a microfilled resin composite and beta-quartz insert. In six groups, contamination or disinfection--latex glove, bare finger, human saliva, 95% ethanol, or LpHse disinfectant--was applied to the insert prior to placement. Latex gloves, bare fingers, and saliva were found to have a detrimental effect on the insert-resin composite interface that could compromise the longevity of the restoration.	{ "pile_set_name": "PubMed Abstracts" }
Despite progress in leukemia therapy, most adult patients with leukemia still die from disease progression. Arsenic trioxide, an inorganic compound, has been approved for the treatment of patients with relapsed or refractory acute promyelocytic leukemia (APL) and is being evaluated as therapy for other leukemia types. Preliminary data from China and the recent experience in the U.S., however, suggest a role for arsenic trioxide in the other hematologic cancers as well. Consequently, the activity of arsenic trioxide as an anti-leukemic agent is currently being investigated in many types of leukemia. Although the results look favorable in terms of the response rate of some of the leukemia types that are being investigated, systemic toxicity of arsenic trioxide is a problem (Soignet et al., 1999; Wiernik et al 1999; Geissler et al., 1999; Rousselot et al., 1999). The only organic arsenical (OA) manufactured for human use, melarsoprol, has been evaluated for antileukemic activity (WO9924029, EP1002537). Unfortunately, this compound is excessively toxic to patients with leukemia at concentrations used for the treatment of trypanosomiasis. Therefore, there is a need to identify arsenic derivatives that can be used for the treatment of hematologic malignancies and cancer in general, that have similar or greater activity and lower toxicity than arsenic trioxide.	{ "pile_set_name": "USPTO Backgrounds" }
Rope dart The rope dart or rope javelin (), also known as Jōhyō in Japanese, is one of the flexible weapons in Chinese martial arts. Other weapons in this family include the meteor hammer, flying claws, Fei Tou flying weight, and chain whip. Although the flexible weapons share similar movements, each weapon has its own specific techniques. The rope dart is a long rope (usually ) with a metal dart attached to one end. This was a weapon from ancient times, which allows the user to throw the dart out at a long-range target and use the rope to pull it back. The rope dart can be used for twining, binding, circling, hitting, piercing, tightening, slashing and other techniques. Rope dart play consists of twining, shooting, and retrieval. Twining and shooting can be done from any joint such as foot, knee, elbow, and neck. The rope is anchored on one hand and played primarily with the other hand. Skillful use of the rope dart can easily trick an opponent because the dart can shoot out very suddenly, from a person beyond immediate reach. Just like the chain whip, excellent hand-eye coordination is a must for the practitioner to use this weapon well. In some Wushu training regimens, the chain whip and Changquan are prerequisites for learning the rope dart. A variation of this weapon is the meteor hammer, which has a blunt weight on the end of the rope. It was used in a similar fashion to the rope dart, and many of the techniques are the same. History The first written description of the rope dart is dated from the Tang Dynasty (618–907 AD). Construction The rope dart is constructed from 4 to 5 parts: dart rings rope or fine chain flags or bright feathers handle (optional) The dart is made of a hard material, usually iron or steel. It can be of variable weight depending on the users preference, and can be variable in shape (conical, triangular prism, pentagonal prism). The rings (usually 4 or 5) are attached to the dart head. The rope is attached to the final ring. Traditionally, the rope was constructed from Chinese rope and covered with wax to minimize friction. In modern times, the rope is often made of a softer synthetic material and covered with talc powder or some other substance to reduce friction. There is at least one flag attached near, or onto the dart head itself to conceal the dart during play and to add control. Additional flags can be attached to the side rings to slow down the dart and increase control. The handle is made from the last piece of rope as a slipknot to attach to the anchor hand's wrist. As performance art While relatively new, rope dart is becoming increasingly popular in being used in the object manipulation scene due to its impressive performances. Because of this, there have been modifications to the original design. Some rope darts have been created to be set alight. A section of fireproof chain between the dart or meteor head and the rope attaches it securely and Kevlar wicks form the flammable head. Other rope darts have heads filled with LED lights. Both of these can be performed in the dark, adding excitement and mystery. In modern media In Rope Dart Instructional DVD Intermediate & Advanced (2013), Master Frank Hatsis, (International Gold Medalist), teaches Rope Dart. In Rope Dart Instructional Series (2007), Master Disco Duck, (Gold Medalist for the 2008 USA Wushu Team, China), teaches Rope Dart. In Heroes of the East (1978), Gordon Liu's character uses a rope dart against a Ninja. In Romeo Must Die (2000), Jet Li's character briefly uses a firehose as a rope dart. In Shanghai Noon (2000), Jackie Chan's character Chon Wang fashions a blunt rope dart with a horseshoe and a length of rope. In 2000's Scooby Doo movie, the character of Fred Jones was shown experimenting with rope dart techniques in the finale. The characters Scorpion and Smoke from the Mortal Kombat series of video games each use a rope dart (or alternately a kunai on a rope) in a special attack that impales and drags opponents closer for a melee attack. * In Mortal Kombat: Shaolin Monks, Scorpion also uses this weapon like a more traditional rope dart. In Super Smash Brothers Melee and Brawl, Princess Zelda, as Sheik, uses a rope dart or chain whip type weapon as her side B attack. In Stormbreaker, Alex uses the rope dart technique to take out four auto wreckers and escape another two. In Ong Bak 2 (2009), one of the villains uses a rope dart to attack the main character Tien (played by Tony Jaa). Tien then proceeds to steal it, and uses it to attack several other villains for a short time. In Kick-Ass, Hit-Girl uses a rope dart to dispatch several opponents when storming the penthouse. In Code Geass, the Chinese mecha Shen-Hu features rope darts mounted in its forearms, which can be electrified for extra damage, or spun rapidly like helicopter blades to generate a shield-like effect. In the animated film Green Lantern: Emerald Knights (2011), Laira Omoto creates two rope dart constructs while fighting her father, Kentor Omoto. In the Assassin's Creed series, the Assassin characters Shao Jun, Edward Kenway, Shay Cormac, Adéwalé, Ratonhnhaké:ton and Arbaaz Mir use rope darts. In the animated series Ultimate Spider-Man, the K'un-Lun ninja Scorpion uses an exaggerated tail-like rope dart against Iron Fist which is later incorporated into his suit tail in battles against Spider-Man and allies as a member of the Sinister Six. In Pulimurugan (2016), Mohanlal's character Murugan uses rope dart as a primary weapon of defense, though the use of the same is animated. In the sixth second-season episode "A Fractured House" of Marvel's Agents of S.H.I.E.L.D., HYDRA operative Marcus Scarlotti uses a thick rope dart as a weapon against S.H.I.E.L.D. agent Melinda May. See also Slungshot – a rope with a weighted end, far shorter, though similar in construction. References Further reading External links Rope Dart Academy Homepage Don Hyun Kiolbassa/Rope Dart Category:Ancient weapons Category:Chinese melee weapons Category:Chain and rope throwing weapons	{ "pile_set_name": "Wikipedia (en)" }
Project Summary The innate immune system has several families of pattern recognition receptors to detect invading pathogens and initiate inflammatory responses to rapidly eliminate the pathogen. The innate immune system also plays an instructive role in induction of adaptive immune responses against virulent pathogens. Toll-like receptors (TLR) are one such family of receptors and their activation in cells of the innate immune system, such as dendritic cells and macrophages, induces secretion of several pro-inflammatory cytokines such as IL-6, IL-12, TNF?, etc. Many of these cytokines play an important role in T cell activation and differentiation. TLR activation also leads to synthesis of a second family of cytokines comprised of IL-1 and IL-18 which are cleaved into active forms and secreted following activation of a different family of cytosolic receptors called NOD like receptors (NLRs). The cytokines IL-1 and IL-18 have major influence in directing T cell activation and differentiation and more importantly use the same signaling components as the TLR signaling pathway. It is becoming clear that IL-1 and IL-18 are the major players in innate control of adaptive immunity and the mechanisms by which they regulate T cell activation and differentiation are not completely understood. Our previous work has shown that IL-R mediated MyD88 dependent signaling is critical for Th17 lineage differentiation in systemic and mucosal immune systems. Th17 cells are crucial for fighting fungal and extracellular bacterial infections and have also been implicating in causing auto-immune diseases such as Rheumatoid Arthritis and Inflammatory Bowel Disease. It is therefore crucial to understand the cellular and molecular mechanisms by which these cells are regulated. In our new studies we have found that IL-1 plays a critical role in regulating effector functions of already primed Th17 memory T cells. We propose to build on these findings and gain a deeper understanding of how IL-1 regulates functioning of Th17 cells and elucidate the physiological significance of IL-1 mediated regulation of Th17 effector functions. In Aim 1, we will understand of the cellular and molecular mechanisms by which IL-1 is made during dendritic cell-memory Th17 cell interactions. In Aim 2, we will elucidate the signaling and molecular mechanisms by which IL-1R signaling in T cells impacts production of IL-17 and related family of cytokines. In Aim 3, we will use in vivo approaches to understand the importance of IL-1R signaling in memory Th17 cell function and examine the role of IL-1 in reactivation of pathogen specific memory Th17 cells as well as memory Th17 cells that cause auto-immunity . These studies will significantly advance our understanding of the role of IL-1 family of cytokines in regulation of CD4 T cell functions. Further more, unraveling the molecular mechanisms by which IL-1 family of cytokines regulate effector and memory T cell functions will not only enhance our understanding of immune responses against pathogens but will aid in development of targeted therapies to dampen inflammatory T cell responses.	{ "pile_set_name": "NIH ExPorter" }
Q: Sending data via a socket from Objective-C to Java I have a Java program (call it Jack) and an Objective-C program (call it Oscar), which I run on the same Mac OS X computer. Oscar sends a string message via a socket to Jack, once per second. For reliability and performance would it be better to maintain an open socket between Jack and Oscar? Or would it be better to repeatedly open a socket, send the message, then close the socket again? A: Keep it open. You are going to need it a lot (once per second), and there's some overhead involved in opening new sockets. Plus, you will be chewing up the heap with new objects until the garbage collector comes by.	{ "pile_set_name": "StackExchange" }
Implicit-shape constancy as a factor in pictorial perception. Schoolboys from the Ivory Coast and from Kenya were tested on a simple task intended to detect the effect of implicit-shape constancy. The presence of such an effect was confirmed. Comparison of two Ivorean subsamples differing in their responses to a request to build a model of a depicted structure showed that those subjects who build flat (2D) models were less influenced by the implicit-shape constancy than those subjects who built three-dimensional structures. This confirms a postulated link between the implicit constancy and perception of pictorial depth.	{ "pile_set_name": "PubMed Abstracts" }
Information and Products by this Faculty Please wait ... Michael R. Whiting, CPA With more than 20 years of accounting, audit, and business advisory services, Michael has serviced clients throughout Michigan as well as internationally. His professional background includes engagements of clients both private and publicly held of diverse sizes and industries. Michael serves as a Director in BDO's Accounting & Reporting Advisory Services group (“ARAS”). Through BDO’s ARAS group, he assists companies with new accounting standards implementation including ASC 842 “Leases” and ASC 606 “Revenue From Contracts With Customers”, complex accounting issues, public and private company reporting matters, and various other technical accounting focused services. Michael is also an Audit Director with extensive experience in various industries such as real estate, professional services, wholesalers, distributors, manufacturing, and technology. Michael’s experience includes work on Sarbanes-Oxley compliance requirements, agreed upon procedures engagements, and other special projects. About The Accounting Continuing Professional Education Network (ACPEN) CPE network, sponsored by State CPA Societies in many states, is dedicated to bringing, highly relevant, interactive, world-class CPE to every CPA in the most convenient and economical ways possible. Please visit acpen.com to learn more. This site uses cookies and other tracking technologies to assist with navigation and your ability to provide feedback, analyze your use of our products and services, and assist with our promotional and marketing efforts. More Information	{ "pile_set_name": "Pile-CC" }
Zombies, Jedi, and the Fight Against Fascism What makes movies ‘political’, and how is what we watch on the big screen related to what we do online, at the ballot box, and in the street? In other words, how do politics and pop culture shape each other? Click here to register. Join film critic and cultural journalist Chauncey K. Robinson and arts educator Michelle P. Kern for a look at movies, Marxism, and the Resistance. Chauncey will examine how film can reflect progressive, but also toxic, messaging that both mirrors and influences our society. She will also deep dive into how the horror genre has been a source of progressive themes, reflecting the terrors of society in creative and at times brutal ways. Michelle will discuss the evolution of political themes in Star Wars, how they’ve been influenced by the events that were contemporary when each series was made, and how they in turn now influence political resistance in current movements. She will pay special attention to how push back against the new series reflects social anxieties that persist in U.S. capitalist culture. Sunday, December 16 8 PM-9 PM Eastern No need to buy a ticket! Just get your favorite movie theater snacks and register here. Author The Communist Party USA is a working class organization founded in 1919 in Chicago, IL. The Communist Party stands for the interests of the American working class and the American people. It stands for our interests in both the present and the future. Solidarity with workers of other countries is also part of our work. We work in coalition with the labor movement, the peace movement, the student movement, organizations fighting for equality and social justice, the environmental movement, immigrants rights groups and the health care for all campaign. But to win a better life for working families, we believe that we must go further. We believe that the American people can replace capitalism with a system that puts people before profit — socialism. We are rooted in our country's revolutionary history and its struggles for democracy. We call for "Bill of Rights" socialism, guaranteeing full individual freedoms. We are a political party of the working class, for the working class, with no corporate sponsors or billionaire backers. Join the generations of workers whose generosity and solidarity sustains the fight for justice.	{ "pile_set_name": "Pile-CC" }
Anti TTHome Update Anti TTHome Update[Only registered and activated users can see links. ]Here I leave a patch to make the trick easier TTHome not ask us to update the TTHome. Spoiler: Update [Only registered and activated users can see links. ] pw: Mazul DOWNLOAD one of the best versions of TTHome. TomTom Home 2.7 This version allows uncheck navcore update (application) you need to edit the file as instructed, or apply the patch below to antiupdate not pass the dangerous versions 2.8 Advertissements I'm in trouble. I uninstalled the actual TTHome; downloaded and installed 2.7 from the above spoiler; applied the patch; run TTHome2 and an error occurred ("server : null"); I ignored it and proceeded, being able to uncheck the TOMTOM WORK (an update to navcore) flag. BUT no map update occurred and, worse, the request to update to 2.9.8 appeared and, if canceled, TTHOME shut down. Where did I mistake ? Furthermore what do you mean by "you need to edit the file as instructed, or apply the patch below to antiupdate " ?? I was unable to find any "instruction" and "below" there is only the spoiler to TT 2.5. I'm in trouble. I uninstalled the actual TTHome; downloaded and installed 2.7 from the above spoiler; applied the patch; run TTHome2 and an error occurred ("server : null"); I ignored it and proceeded, being able to uncheck the TOMTOM WORK (an update to navcore) flag. BUT no map update occurred and, worse, the request to update to 2.9.8 appeared and, if canceled, TTHOME shut down. Where did I mistake ? Furthermore what do you mean by "you need to edit the file as instructed, or apply the patch below to antiupdate " ?? I was unable to find any "instruction" and "below" there is only the spoiler to TT 2.5. Please, help Hi all unopened tomtom home made home, if so there is this error. Apply the patch before starting tomtom home Hi look to do this before starting tomtom home:-Uninstalled the current version -We urge the desired version "in the last step unchecking Start TomTom Home" If we leave things like the Home return us to say that there are more modern version and would like to start. So let's make believe the program to have the latest version. To deceive the home will: (The path may change depending on operating system) In my Pc with windows Vista is on this route have already seen that the above does not help me in my - C: \ Program Files \ TomTom HOME 2 \ xul \ application.ini - Open the file with Notepad or Wordpad (looks better with worpad) and look for the line: ; This field specifies your application's version. This field is optional. Version = (put the numbers in the version we installed) That line-change it to: ; This field specifies your application's version. This field is optional. Version = 3.9.7.3256 When looking for Home updates, the program believe that already the latest version, and therefore does not offer upgrade version. NOTE: Sometimes depending on the (Windows 7) operating system and whether or not you running it as administrator, will not let you change the files for this you have to click the right mouse button and run or open as administrator, this way allows you to make and save changes If it still does not let you edit the file, copiŠis the file to your desktop and once you have it changed what ye turn to paste on your site. greeting [Only registered and activated users can see links. ] How to unhide links: After clicking LIKE this post, hidden links will be available.[Only registered and activated users can see links. ] We use cookies to store session information to facilitate remembering your login information, to allow you to save website preferences, to personalise content and ads, to provide social media features and to analyse our traffic. We also share information about your use of our site with our social media, advertising and analytics partners.	{ "pile_set_name": "Pile-CC" }
Q: React Native - How do I specify state in tests? I am currently working on a React Native component that uses local state to control some UI elements, ie, some elements are only rendered if some values in state are set to true. These values change depending on clicks within the component. Is there a way for me to specify initial state when testing using react's TestRenderer? If not, how could I go around to testing this? I'd like to be able to render the component for certain states and test over it. Any helpful input is very much appreciated. I can provide more detail if necessary. Thanks in advance. EDIT: Adding an example illustrating my code. This is not my component code but it illustrates its behavior: interface IMyComponentProps { ... } interface IMyComponentState { showForm: boolean; } export class MyComponent extends React.Component<IMyComponentProps, IMyComponentState> { constructor(props: any) { super(props); // showForm is initially false this.state = { showForm: false, }; } public render() { // if showForm is true then render my form component if (this.state.showForm) { return <FormComponent />; } else { // otherwise render button that changes the state to showForm: true // and causes a re-render return <Button onClick={this.buttonClickFn} />; } } private buttonClickFn = () => this.setState({...this.state, showForm: true}); } A: The state can be directly set for testing purposes: componentInstance.state.showForm = true; componentInstance.forceUpdate();	{ "pile_set_name": "StackExchange" }
KZYP KZYP may refer to: KZYP (AM), a radio station (1310 AM) licensed to serve Malvern, Arkansas, United States KZYP (defunct), a defunct radio station (99.3 FM) formerly licensed to serve Pine Bluff, Arkansas	{ "pile_set_name": "Wikipedia (en)" }
Kumrova Vas Kumrova Vas (; or Kumrovo, or Kummersdorf, Gottscheerish: Kümmrdoarf) is a remote abandoned settlement in the Municipality of Kočevje in southern Slovenia. The area is part of the traditional region of Lower Carniola and is now included in the Southeast Slovenia Statistical Region. Its territory is now part of the village of Svetli Potok. Name Both the Slovene name Kumrova vas and German name Kummer(s)dorf literally mean 'Kummer village'. It has been suggested that the root Kummer is related to the dialect world Kümar 'impoverished, pitiable person' or to the surname Kummer. The possible designation of the settlement as an impoverished place to live is similar to the naming of the settlements of Slaba Gorica ('poor hill'), Sušje ('dry, drought'), and Verderb ('deterioration'). History Kumrova Vas was a Gottschee German village. In the land registry of 1574, the settlement had three full farms divided into six half-farms and nine owners, corresponding to a population between 32 and 36. In the 1770 census there were 13 houses in the village. The village had a maximum population of 87 people in 14 houses in 1869. In the 19th century, the village had a small industry making woolen coats. On the eve of the Second World War, Kumrova Vas had 10 houses and a population of 32. At the time, the economy of the village was based on agriculture, raising livestock, and peddling. The original ethnic German population, consisting of 25 people from nine families, was evicted early in the war. The village was burned repeatedly by Italian troops between May and August 1942. In late June 1942, the Yugoslav Partisans established their Medical Dressing Station No. 3 here for a week before relocating it to a forestry cabin at Travnik Hill in Kočevski Rog. The village was never rebuilt after the war. Religious heritage A church dedicated to the Holy Name of Jesus stood to the east above Kumrova Vas, dating from 1708. The site was first used as a fortification during the Ottoman wars in Europe, and was later converted into a church. The year 1798, marking a renovation of the church, was carved into the semicircular entryway. The shingled roof of the bell tower burned during a lightning strike in 1865. The church had three altars by the mid-18th century, dedicated to the Holy Name of Jesus, Christ on the Via Dolorosa, and Christ on the Mount of Olives. The church was remodeled in 1933. The church was not repaired after the war and its furnishings disappeared. The location of the church's statues and paintings is unknown today. A small chapel dedicated to the Precious Blood stood northeast of the village. It had a polygonal chancel walled on three sides and a wooden bell-cot over the entrance. Two bells, cast in 1607 and 1839, hung in the bell-cot until 1917. The smaller one bore the inscription Zur Ehre Gottes goß mich Elias Sombrath in Laibach 1603 ('I was cast for the glory of God by Elias Sombrath in Ljubljana, 1603'). The chapel was destroyed during the Second World War and was not rebuilt. Notable people Notable people that were born or lived in Kumrova Vas include: Josef Stalzer, a well-known hermit from Staro Brezje, who lived in a cell near the church from 1837 to 1855 References External links Kumrova Vas on Geopedia Pre–World War II map of Kumrova Vas with oeconyms and family names Category:Former populated places in the Municipality of Kočevje	{ "pile_set_name": "Wikipedia (en)" }
NOTE, BOBBYSIX HAS MOVED. PLEASE VISIT OUR NEW SITE INSTEAD, WHERE YOU WILL FIND SO MUCH AWESOME CONTENT THAT YOUR EYES WON'T KNOW WHERE TO LOOK FIRST: SOMETHINGYOUSAID.COM Sunday, November 22, 2009 Vote For Owl and the Grapes! Firstly, the bad news: Bobbysix.com has not been nominated for an Australian Fashion Award. Surprising I know. However, the magnificent Owl and the Grapes has been nominated as Best Australian Fashion Blog! So please take 2 seconds out of your day to vote. Go here, click on the Best Fashion Blog category and vote for Owl and the Grapes! Voting is open 'till 20th December. Thanks!	{ "pile_set_name": "Pile-CC" }
Drupal 8; contribution; Shorten URL's module As a college task I have to contribute to a module converting it to a Drupal 8 version. And for that I ask the Drupal Community permission to do this, and to start as soon as possible when I have time.	{ "pile_set_name": "Pile-CC" }
{{ content }}	{ "pile_set_name": "Github" }
Q: Issues with pandas install - running several versions of python I'm having issues with installing the panda library. I'm currently using snakemake with Python version 2.7 and 3.4 under LMDE. I've tried the following: pip install pandas which doesn't work, as I get the following error: No module named 'pandas' I figured it is because snakemake is based on python 3, and I tried solutions from this post. This one not working (I don't quite get the concept of virtualenv anyway): apt-get install python-virtualenv virtualenvwrapper mkvirtualenv -p python3 pandas_env pip install pandas Then I tried: sudo apt-get install python3-pandas It worked fine but then I got this error: parser_f() got an unexpected keyword argument 'skip_blank_lines' From this post it looks like a version problem, which should be > 0.15. Last command said it installed pandas 0.14, but when I checked here's what I got: >>> import pandas as pd >>> pd.__version__ '0.16.2' I'm getting stuck here, between python versions and pandas versions I don't know what to do. Any help would be greatly appreciated. A: OK so it seems it makes a difference to install a python lib with pip whether I use sudo as myself or as root?... I had done $ sudo pip install pandas Now I did $ sudo pip uninstall pandas $ su - # pip install pandas And now it seems to work perfectly fine! Is this normal though?	{ "pile_set_name": "StackExchange" }
Satsuma Loans Satsuma Loans (a trading name of Provident Personal Credit) is an online-only loan provider offering short-term loans. It was launched by doorstep lender Provident Financial in 2013. Satsuma Loans charges a typical annual percentage rate of 991% , with a maximum interest rate of 1,575%. Satsuma lends up to £1,000 to first time customers which can be borrowed over a 12-month period, incurring an interest charge of £990 on a £1,000 loan. Satsuma Loans offer fixed weekly or monthly repayment plans and claim that there are no hidden fees or charges with their loans. At the time of its launch Provident described Satsuma Loans as an 'antidote' to payday lenders, as the product allows the loans to be repaid in instalments. This is Money however noted that "irrespective of the time it takes to pay off, this isn't a cheap loan" and quoted financial author Carl Packman suggesting that "this product is capitalising on disquiet about payday lending - but we should remember home credit operators like Provident are often as bad." Satsuma had £5 million of loans as of 2015, increasing from £1.8 million the previous year. __TOC__ Sponsorship Between 2014 and 2016 Satsuma Loans sponsored RFU Championship side Yorkshire Carnegie in a deal worth £600,000. In 2016 it was announced that Satsuma Loans would become an official partner of Sunderland A.F.C. This prompted Sharon Hodgson, the MP for Washington and Sunderland West, to write to the club warning that associating themselves with a high-interest lender would undermine their positive community engagement work. References See also Payday loans in the United Kingdom Category:Financial services companies of England	{ "pile_set_name": "Wikipedia (en)" }
Dragør Municipality Dragør Kommune () is a municipality (Danish, kommune) in Region Hovedstaden on the southern coast of the island of Amager just east of Zealand (Sjælland) in eastern Denmark. The municipality covers an area of 18.41 km² (2013), and has a population of 14,028 (1 January 2015). Its mayor is Eik Dahl Bidstrup, a member of the agrarian liberal Venstre (Denmark). 1970 Danish Municipal Reform Not until four years after the 1970 Danish Municipal Reform on 1 April 1974 two new municipalities were formed in Copenhagen County, namely Dragør Municipality, formed by the merger of Dragør (an independent parish from 1 April 1954) and Store Magleby parishes and Høje-Taastrup Municipality, which from that date also included Sengeløse parish (which - as an already existing parish - was also made an independent municipality from 1 April 1970 until 31 March 1974; but it was considered too small to remain as an independent municipality). The inhabitants would have preferred to remain as independent municipalities. Store Magleby, which was larger in area than Dragør, had a large number of subdivisions (Danish (singular): parcel;udstykning) with owner-occupied homes built on the boundary with Dragør (as far away from the noise as possible from planes landing at Copenhagen Airport, and taking restrictions in building regulations (inside city (built-up area) limits versus outside city limits) into consideration) before the merger. Because the voters of Store Magleby and Sengeløse were almost exclusively owner-occupiers, who voted center-rightwing, whereas Høje-Taastrup Municipality and Dragør Municipality to a large extent consisted of tenants who rented their apartments and who voted center-leftwing, there were heated debates and reluctance among the voters of Store Magleby and Sengeløse about joining the new municipalities. This was because the center-rightwing voters would be in a minority at elections for their local councils. Parishes Dragør parish is surrounded by Store Magleby parish to the north, south, and west and the strait of Øresund to the east, and Dragør parish thus does not border the neighboring Tårnby municipality. Dragør parish has an area of only 156 hectares (1.56 square km;0.6 sq mi), 8.6% of Dragør municipality's area, as opposed to Store Magleby parish's 1602 hectares, the latter accounting for more than 88% of Dragør municipality's area. A part of Copenhagen Airport accounts for 56 hectares, 3% of Dragør municipality, which is outside of parish jurisdiction and taxation. With 4144 people, 29.77% of the population, recorded as living there on 1 January 2013, Dragør parish has a population density of 2656 persons per square km (6880/sq mi), Store Magleby parish with 9737 people, 69.96% of the population, has a density of 607.8 persons per square km (1574.2/sq mi). Thirty-six persons were recorded as not having a fixed address. Overview The main town is Dragør. The seat of the town hall is Store Magleby, which easily can house such a large building. Its only neighboring municipality is Tårnby to the north. To the east and south is the Øresund, the strait that separates Zealand and Amager from Sweden. To the southwest is Køge Bay (Køge Bugt). Dragør Municipality was not merged with any adjacent municipality under the municipal reform of 2007, as it agreed to enter into a "municipal cooperation agreement" with Tårnby Municipality. Economy Prior to its dissolution, Maersk Air had its headquarters in Dragør in the municipality. When it existed, Sterling Airlines had its head office at Copenhagen Airport South in Dragør. References Municipal statistics: NetBorger Kommunefakta, delivered from KMD aka Kommunedata (Municipal Data) Municipal mergers and neighbors: Eniro new municipalities map External links Municipality's official website Visit Dragør website Category:Municipalities in the Capital Region of Denmark Category:Municipalities of Denmark Category:Copenhagen metropolitan area	{ "pile_set_name": "Wikipedia (en)" }
List of siege engines This is a list of siege engines invented through history. A siege engine is a weapon used to destroy fortifications such as walls, castles, bunkers and fortified gates. By age, oldest to newest Further reading Siege engine Ballista Battering ram Petrary Siege tower References Category:Weapons by period Category:Siege engines	{ "pile_set_name": "Wikipedia (en)" }
Relâche Relâche is French for "cancellation", "theater dark", or "no performance today". Relâche (ballet) music by Erik Satie (1924) Relâche (musical group), an American contemporary classical music ensemble from Philadelphia, Pennsylvania fr:Relâche (ballet) ja:本日休演	{ "pile_set_name": "Wikipedia (en)" }
Introduction {#Sec1} ============ Pompe disease, also known as acid maltase deficiency (AMD) or glycogen storage disease type II (GSDII), is a rare autosomal recessive disorder of glycogen metabolism caused by insufficient activity of the enzyme acid alpha-glucosidase (GAA). There are two forms of the disease: infantile-onset Pompe disease (IOPD; aged \<1 year with cardiomyopathy) and late-onset Pompe disease (LOPD; \>1 year of age through to adulthood or \<1 year without cardiomyopathy). The worldwide incidence of both forms of the disease is commonly reported to be 1 in 40,000 \[[@CR1]\], however prospective trials suggest the incidence may be as high as approximately 1 in 9,000 \[[@CR2], [@CR3]\]. Myozyme® (alglucosidase alfa) was approved for the treatment of Pompe disease in Europe and the United States in 2006 and has changed the management of Pompe disease, improving the symptoms of the disease in many, but not all, patients \[[@CR4]\]. Additionally, enzyme replacement therapy (ERT) with alglucosidase alfa extends life expectancy in patients with LOPD \[[@CR5]\]. A number of guidelines exist for the diagnosis and treatment of LOPD \[[@CR6]--[@CR8]\]; however these do not address the challenges faced by the Middle East and North Africa (MENA) region in the diagnosis and treatment of LOPD, namely delayed diagnosis, access to diagnostic tools, and access to treatment. There is, therefore, a need for region-specific recommendations for the diagnosis and treatment of LOPD which assess the latest available literature and tailor it to the region with due consideration of local experiences and challenges. The objective of this paper is to provide clinical guidelines on the diagnosis and treatment of LOPD in the MENA region. Methods {#Sec2} ======= A panel of experts met to develop consensus recommendations to aid diagnosis and treatment of infantile- and late-onset Pompe disease in the MENA region. The panel of physicians from across the MENA region included experts from different specialties -- adult and pediatric neurology, metabolic diseases, genetics, pediatric cardiology, and neuropathology -- all with expertise in the diagnosis and/or management of Pompe disease. A literature review was performed prior to the meeting. A search for relevant articles including randomized control trials, review articles, and most recent international guidelines on the diagnosis and treatment of LOPD was undertaken using PubMed. The search terms included: late onset Pompe disease, glycogen storage disease type II, lysosomal storage disorders, acid alpha-glucosidase deficiency, and acid maltase deficiency. The panel critically analyzed and discussed these articles at the meeting. The validity, clinical relevance, and applicability of the evidence for LOPD in the MENA region were discussed. After considering the evidence, the panel achieved a consensus on a number of recommendations that are supported by best scientific evidence. Background {#Sec3} ========== Pompe disease was first characterized in 1932 by Joannes C. Pompe, who described glycogen accumulation in cardiac muscle in a 7-month-old girl who died \[[@CR9]\]. Pompe disease was first categorized as GSDII by G.T. Cori in 1954 \[[@CR10]\], and further understanding of the disease was achieved with the discovery of lysosomes in 1955 by Christian de Duve \[[@CR11], [@CR12]\]. In 1963, Henri Hers identified GAA as the enzyme that is deficient in Pompe patients and therefore responsible for Pompe disease \[[@CR13]\]. Following the discovery of GAA deficiency as the cause of Pompe disease, a number of enzyme replacement trials have been conducted. In 1964, Baudhuin and colleagues intramuscularly injected an extract of the fungus Aspergillus niger, which was shown to contain GAA, into a patient with abnormal lysosomes; however the treatment did not demonstrate any appreciable change in the lysosomes \[[@CR14]\]. In 1974, ERT using enzymes purified from a human source were administered to two patients with Gaucher's disease \[[@CR15]\]. Exogenous glucocerebrosidase was found to cause a definite decrease in the quantity of accumulated lipids, but the results were largely disappointing. The first successful ERT of a lysosomal storage disorder in humans was achieved in 1991 when Barton and colleagues reported the results of infusion of macrophage-targeted human placental glucocerebrosidase into 12 patients with type 1 Gaucher's disease \[[@CR16]\]. In the same year, the first successful in vivo study of GAA ERT was reported \[[@CR17]\]. Van der Ploeg and colleagues reported that a human placenta-derived GAA delivered by a mannose 6-phosphate receptor-mediated ERT had resulted in cardiac uptake in mice, offering the potential for a treatment for Pompe disease. This potential was realized in 2001 when the first clinical studies of ERT infusion in IOPD patients were published \[[@CR18], [@CR19]\]. These showed that recombinant human GAA (rhGAA) derived from either Chinese hamster ovary (CHO) cells or transgenic rabbit milk is capable of improving cardiac and skeletal muscle function. Longer term studies confirmed the tolerability, safety, and efficacy of ERT in Pompe disease \[[@CR20], [@CR21]\], resulting in the regulatory approvals of alglucosidase alfa for the treatment of Pompe disease in 2006 \[[@CR22]\]. The first randomized controlled study of ERT in LOPD patients was published in 2010 \[[@CR23]\] and demonstrated that alglucosidase alfa leads to stabilization of neuromuscular deficits as well as some degree of functional improvement \[[@CR23], [@CR24]\]. ERT with alglucosidase alfa is not a cure for Pompe disease, but it can greatly modify or attenuate the phenotype, improving clinical outcome, quality of life (QOL), and survival. Epidemiology {#Sec4} ============ The combined incidence of both forms of Pompe disease varies depending on ethnicity and geographic region, ranging from 1 in 14,000 to 1 in 600,000 reported in African American and Portuguese populations, respectively \[[@CR25]--[@CR27]\]. The worldwide incidence of both forms of the disease is commonly reported to be 1 in 40,000 \[[@CR1]\]. The frequency of LOPD is estimated at 1 in 57,000 \[[@CR28]\]. However, two prospective trials performed in the context of newborn screening challenge this. The incidence of LOPD in Taiwan based on a prospective newborn screening study is 1/26,466 \[[@CR2]\] and the overall incidence of Pompe disease in Austria based on a prospective newborn screening study is 1/8,684 live births \[[@CR3]\]. There are no late-onset incidence studies in the MENA region; however the prevalence of IOPD in Emiratis has been reported as 2.66 per 100,000 based on UAE experience from two centers and is likely much higher \[[@CR29]\]. Additionally, the high degree of consanguinity in the region results in higher incidence of autosomal recessive diseases in general \[[@CR30]\]. Pathophysiology {#Sec5} =============== Pompe disease is a result of mutations in the GAA gene, which is located on the long arm of chromosome 17 (17q25.2-q25.3) \[[@CR31], [@CR32]\] and encodes the 105-kDa GAA enzyme \[[@CR33]\]. Mutations in the gene lead to deficiency in the lysosomal enzyme GAA, causing accumulation of lysosomal and non-lysosomal glycogen in multiple tissues \[[@CR34]\]. Lysosomal enlargement and rupture, as well as autophagic accumulation, contribute to the progressive myopathy in the disease, with autophagic accumulation causing skeletal muscle destruction in LOPD (Fig. [1](#Fig1){ref-type="fig"}).Fig. 1Pathophysiology of late-onset Pompe disease. Abbreviations: GAA, acid alpha-glucosidase Due to the broad clinical spectrum of the presenting phenotype, a number of differential diagnoses for Pompe disease should be considered. These differential diagnoses and their features common to Pompe disease are summarized in Table [1](#Tab1){ref-type="table"}.Table 1Differential diagnosis of LOPDDifferential conditionCommon symptomsLimb--girdle muscular dystrophy (LGMD)Progressive muscle weakness in the pelvis, legs, and shoulders; elevated CKBecker muscular dystrophy (BMD)Progressive proximal muscle weakness, prominent quadriceps weakness, calf hypertrophy, elevated CK, cardiomyopathySelenoprotein N1-related myopathySpinal rigidity, respiratory failure, muscle hypotrophyMyasthenia gravisPtosis, ophthalmoplegia, bulbar dysfunction, proximal muscle weakness, fluctuating courseSpinal muscular atrophyProgressive proximal muscle weakness and atrophy, respiratory failure, postural tremor, mild elevated CKPolymyositisUnexplained muscle weakness with elevated CKGlycogen storage diseases: IIIa (Debrancher deficiency/Cori), IV (branching enzyme deficiency/Anderson disease), VHypotonia, hepatomegaly and hepatic failure, muscle weakness with distal involvement, elevated CKDanon diseaseHypertrophic cardiomyopathy, skeletal muscle myopathyMitochondrial myopathiesHyptonia, hyporeflexia, hepatomegaly. Some forms with hypertrophic cardiomyopathy, muscle weakness, external ophthalmoplegia, elevated CKLipid storage myopathiesFluctuating muscle weakness with respiratory involvement, sometimes bulbar weakness, elevated CKCK creatine kinase. Adapted by permission from Macmillan Publishers Ltd: Genet Med. 2006;8(5):267--88 \[[@CR52]\] © 2006 Clinical phenotype {#Sec6} ================== LOPD has a wide spectrum of signs and symptoms \[[@CR1]\]. While the age of symptom onset has been reported from \<12 months of age to 70+ years, the average age at onset of symptoms is between 29 and 33 years, while the mean age at initial diagnosis is 36--43 years \[[@CR35]--[@CR38]\]. LOPD is a multisystem disorder which typically manifests as limb--girdle muscle weakness, respiratory symptoms, and progression to respiratory insufficiency due to diaphragmatic and intercostal muscle weakness. The phenotype can include varying degrees: limb--girdle muscle weakness, scapular winging, neck flexor weakness, abdominal wall musculature involvement, or a lordotic waddling gait \[[@CR1]\]. Symptoms may include rigid spine syndrome (RSS), scoliosis, low body mass \[[@CR38]\], and asymptomatic hyperCKemia \[[@CR39]\]. Other symptoms may include asymmetrical ptosis, tongue weakness, and dysphagia \[[@CR35], [@CR38], [@CR40], [@CR41]\]. Myalgia and fatigue are important symptoms as they are sometimes the presenting complaint \[[@CR35]\]. Cardiac symptoms are common in IOPD and while cardiac involvement in LOPD remains somewhat controversial with conflicting reports found in the literature, Wolff--Parkinson--White syndrome has been implicated. A study of 46 consecutive adult patients with LOPD suggests that major cardiac abnormalities are rare \[[@CR42]\]. However, another study of the clinical and neurophysiological spectrum of 38 LOPD patients identified three subjects who suffered from arrhythmias due to Wolff--Parkinson--White syndrome despite no echocardiographic signs of cardiomyopathy \[[@CR1]\]. Cerebral aneurysms have been reported as complications in LOPD patients, and may be increased in incidence over the general population, however this is not certain \[[@CR43], [@CR44]\]. Hearing loss is often described in classic IOPD patients. While it is rarer in LOPD, there have been reports of mild hearing loss due to stapedius muscle or cochlear involvement \[[@CR45], [@CR46]\]. Low bone mineral density, scoliosis, and osteoporosis have also been reported in LOPD patients. A study of 46 patients found that bone mineral density was significantly lower in Pompe patients than in healthy individuals, with 26 % of patients classified as having osteoporosis/low bone mass for chronological age; however this may be a consequence of weakness and reduced mobility, as seen in muscular disorders, and not specific for LOPD \[[@CR47]\]. Recent studies have identified LOPD in both symptomatic patients with muscle weakness and patients presenting with presymptomatic hyperCKemia \[[@CR48]--[@CR50]\]. Diagnosis {#Sec7} ========= With such a wide variation in age of onset and a non-specific symptoms complex, a high degree of clinical suspicion is necessary to diagnose patients with LOPD and a low threshold should be used for clinical screening with dried blood spot (DBS) testing. The diagnosis should be suspected on the clinical presentation and phenotype and the evaluation should then ensue. Clinical evaluation {#Sec8} ------------------- ### Creatine kinase {#Sec9} Serum creatine kinase (CK) is elevated in 95 % of patients with LOPD \[[@CR51]\], however the range can vary from normal (60--305 IU/L) to 15 times the upper limit of normal. Concurrent elevation of alanine transaminase (ALT), aspartate transaminase (AST), and lactate dehydrogenase (LDH) from muscle sources are frequently detected \[[@CR52]\]. Serum CK may be elevated in presymtomatic LOPD patients \[[@CR48], [@CR49]\]. ### Forced vital capacity {#Sec10} The forced vital capacity (FVC) should be performed in the upright and supine positions and can be done with a hand-held spirometer. In most normal subjects, FVC in the supine position is 5--10 % less than when upright; a drop of ≥10 % is suggestive of diaphragmatic weakness and a drop \>30 % is associated with severe diaphragmatic weakness \[[@CR53], [@CR54]\]. ### Electromyography {#Sec11} A conventional electromyograph (EMG) may be normal in patients with LOPD, however studies suggest that approximately 70 % may have a myopathic EMG pattern \[[@CR1]\]. Studying the more proximal muscles, including the paraspinal muscles, has been shown to be more likely to reveal abnormalities. In addition to typical myopathic features, myotonic discharges without clinical myotonia have also been described sometimes occurring only in paraspinal muscles \[[@CR55]\]. In addition, fibrillation potentials, positive sharp waves, and complex repetitive discharges may be seen \[[@CR41]\]. Nerve conduction studies in Pompe disease patients are typically normal \[[@CR1]\]. ### Dried blood spot testing {#Sec12} When available, DBS testing for GAA activity is the preferred screening test for LOPD as it is a simple, inexpensive, and noninvasive assay \[[@CR56]\]. Briefly, a blood spot obtained from the patient is assayed for GAA activity using spectrophoto-fluorimetry with recombinant GAA used as a calibrator for immuno-quantification \[[@CR57]\]. The limitations of the DBS test include logistics, a lack of local facilities to perform the analysis, long turnaround times for testing in some regions of the world, and false-positive results. A positive DBS is not diagnostic for LOPD and a second test should be performed to confirm the diagnosis. These confirmatory tests can include lymphocytes for GAA analysis, fibroblast cultures again assayed for GAA, gene sequencing, or muscle biopsy with or without GAA enzyme analysis. The diagnostic tests for LOPD are summarized in Table [2](#Tab2){ref-type="table"}.Table 2Summary of diagnostic tests for LOPDTestPompe presentationCreatine kinaseVaries from normal to 15 times the upper limit of normalAlanine transaminase and aspartate transaminaseFrequently elevatedForced vital capacityReduced in most patients. A drop of ≥10 % in supine versus upright is suggestive of diaphragmatic weakness and a drop \>30 % is associated with severe diaphragmatic weaknessElectromyographyMyopathic EMG may be present, particularly in proximal muscles such as the paraspinal muscles. Myotonic discharges without clinical myotonia, fibrillation potentials, positive sharp waves, and complex repetitive discharges may also be seenDried blood spotGAA activity reducedEMG electromyography, GAA acid alpha-glucosidase ### Confirmatory tests {#Sec13} #### Lymphocytes for GAA {#FPar1} GAA activity cannot be assayed in mixed leukocytes as neutrophils contain maltase gluco-amylase (MGA) which leads to false-negative results \[[@CR56]\]. Lymphocytes do not contain MGA and therefore LOPD can be diagnosed by assaying GAA in purified lymphocyte preparations. Testing lymphocytes for GAA is minimally invasive and has a rapid turnaround time. If successfully performed, a positive result may preclude the need for a more invasive test such as skin or muscle biopsy. The major limitation is that isolation and purification must be performed within 30 minutes and there is a lack of facilities and appropriately trained staff in most centers. Inclusion of acarbose is recommended to eliminate the interference by MGA when neutrophils are present \[[@CR56]\]. #### Fibroblast cultures {#FPar2} Enzyme analysis of cultured fibroblasts is the gold standard test for diagnosis. A skin biopsy typically requires local anesthetic and requires 4--6 weeks of cell culture, after which an assay is used to quantify GAA activity. In children and adults with Pompe disease, residual GAA activity is approximately 2--40 % of normal activity \[[@CR52]\]. A key advantage is that it may preclude the need for an invasive muscle biopsy; however, the main limitations are the possible failure of fibroblast growth, the long turnaround time (usually 6--8 weeks) and the need for cell culture and enzyme assay facilities. #### Genetic testing {#FPar3} GAA is the only gene in which mutations are known to cause LOPD. Numerous pathogenic variants of the gene have been reported \[[@CR58]\]. Mutations are spread across the gene, with particular mutations more common in some populations due to founder effects \[[@CR52]\]. Methods for detecting mutations include targeted mutational analysis, full sequence analysis, and deletion/duplication analysis; however none of these have a 100 % mutation detection frequency \[[@CR25]\]. The limitations of genetic testing include time, cost, and specificity. #### Muscle biopsy {#FPar4} Muscle biopsy is widely practiced in the assessment of patients with neuromuscular disorders. It can be used as a diagnostic or a confirmatory test in LOPD (Figs. [2](#Fig2){ref-type="fig"} and [3](#Fig3){ref-type="fig"}). The procedure is invasive but most adult patients only require local anesthesia. The muscle specimen must be immediately frozen in isopentane, cooled in liquid nitrogen, and shipped on dry ice. Muscle biopsy in LOPD shows the presence of vacuoles that stain positively for glycogen, with accumulation in the lysosomes and cytosol observed in the advanced stages of the disease \[[@CR52]\]. The limitations of muscle biopsy include the potential for false-negative results, the scarcity of facilities and personnel to process and interpret the specimens, and the invasive nature of the procedure.Fig. 2Biopsy from right vastus lateralis of a 46-year-old woman with LOPD. She had a long history of muscle weakness presenting with respiratory insufficiency. a Prominent fiber size variation and excess internalized nuclei with variable-sized subsarcolemmal and cytoplasmic vacuoles (H&E stain x200). b Pronounced vacuolation of many fibers, some vacuoles are slightly red-rimmed (modified Gomori trichrome stain x200). c Pronounced glycogen accumulation as intense staining of subsarcolemmal and cytoplasmic vacuoles (PAS stain x200). d Immunolabeling of multiple membrane-bound cytoplasmic vacuoles with dystrophin (Dystrophin 1, Biogenex Co. x200). Images provided by Dr Yalda NilipourFig. 3Muscle biopsy from left brachioradialis of a 40-year-old man with LOPD. He had had progressive limb--girdle muscle weakness since adulthood. a Slight variation in fiber size and some internalized nuclei with tiny cytoplasmic vacuoles in few fibers (H&E x400). b Only a little accumulation of glycogen in few fibers as punctate staining (PAS x400). c Tiny cytoplasmic vacuoles in few fibers. (Gomori trichrome x400). d Immunolabeling of dystrophin. Dot-like labelling of tiny membrane-bound cytoplasmic vacuoles in some fibers (Dystrophin 1, Biogenex Co. x400). Images provided by Dr Yalda Nilipour In some cases, muscle biopsy can be normal or show non-specific changes using routine techniques of evaluation. Non-specific changes include lobulated or globular fibers, moth-eaten fibers, degenerative fibers, or even necrotic fibers and ragged-red-fibers or COX-negative fibers \[[@CR59]\]. Up to 20--30 % of individuals with LOPD with documented decreased enzyme activity may not show muscle-specific changes and therefore a non-diagnostic muscle biopsy of adult patients does not exclude Pompe disease \[[@CR60]\]. Biopsies from patients with LOPD have been read as normal, polymyositis, and others. #### Whole body/muscle magnetic resonance imaging {#FPar5} Where it is available and feasible, whole body magnetic resonance imaging (MRI) can be used to better define the degree and distribution of muscle involvement and aid in the selection of muscles for biopsy \[[@CR61]\]. Furthermore, early recognition of respiratory muscle involvement using MRI could allow an early start of ERT \[[@CR62]\]. Although whole body MRI is now being included in clinical trials to monitor patients, its use in clinical practice is not yet recommended for monitoring individual patients. Diagnostic dilemmas {#Sec14} ------------------- It has previously been reported that diagnosis of Pompe disease is a diagnostic dilemma in itself due to the rarity of the disease and the non-specific phenotype \[[@CR52]\]. A number of diagnostic dilemmas are faced in the region. Mutation-related dilemmas include the identification of new variants with an unknown significance for pathology which requires the use of clinical findings and other biochemical parameters for diagnosis. Other diagnostic dilemmas include a positive screening test and only one mutation by genetic testing and positive DBS with unusual clinical features. In these cases the gold standard of fibroblast culture is recommended. Consensus recommendations {#Sec15} ------------------------- The experts agreed that the diagnosis of LOPD can be difficult, as the phenotype is heterogeneous and may resemble the clinical features of a number of other neuromuscular disorders; a high clinical suspicion was considered important for the diagnosis of this disease. Fig. [4](#Fig4){ref-type="fig"} displays an algorithm for the diagnosis of LOPD as per the experts' recommendations. In patients who are symptomatic and have a known case and mutation within the family, investigation should begin with molecular testing.Fig. 4Algorithm for the diagnosis of LOPD. Abbreviations: ALT, alanine transaminase; AST, aspartate transaminase; CK, creatine kinase; DBS, dried blood spot; EMG, electromyography; FVC, forced vital capacity; GAA, acid alpha-glucosidase. \Alternative diagnosis made. Adapted with permission from AANEM. Diagnostic Criteria for Late-Onset (Childhood and Adult) Pompe Disease. Muscle Nerve. 2009;40:149--160 \[[@CR107]\] © 2009 Wiley Periodicals, Inc Muscle weakness, high serum CK values (up to 15-fold) and a decline in pulmonary function were considered by the experts as criteria for suspicion of LOPD. Consensus was achieved among the experts that a DBS screening test should be conducted in patients with unexplained weakness or suspected LOPD in the MENA region. It was agreed that one of the following confirmatory tests should be conducted after obtaining a positive DBS screening test or when DBS is inconclusive and there is a high degree of clinical suspicion: enzymatic assay on lymphocytes or fibroblasts, genotyping, or muscle biopsy. GAA enzymatic analysis of fibroblasts was selected as the gold standard, although the logistics of this test were considered a limitation (Table [3](#Tab3){ref-type="table"}). The experts agreed and recommend that local facilities need to be developed in each country to perform the required testing.Table 3Summary of confirmatory tests for LOPDTestDescriptionPompe presentationLymphocytes for GAAGAA assayed in purified lymphocyte preparationsGAA activity reducedFibroblast cultures for GAAGAA assayed in cultured fibroblasts from skin biopsyGAA activity reducedGenetic testingTargeted mutational analysis, full sequence analysis, or deletion/duplication analysisPathogenic mutations may be detectedMuscle biopsyHistology or immuno-histology of muscle biopsy samplesVacuoles that stain positively for glycogen, with accumulation in the lysosomes and cytosol observed in the advanced stages of the diseaseGAA activity reducedMay be normal or show non-specific changesGAA* acid alpha-glucosidase Treatment {#Sec16} ========= Enzyme replacement therapy {#Sec17} -------------------------- ERT with alglucosidase alfa has shown disease stabilization or improvement in patients with LOPD. The Late-Onset Treatment Study (LOTS), which investigated the effect of alglucosidase alfa in 90 LOPD patients, identified improved walking distance and stabilization in pulmonary function in the first 78 weeks of treatment, which was maintained at 104 weeks \[[@CR23]\]. In a systematic literature review of LOPD therapy, it was reported that in 368 patients from 21 studies, at least two-thirds were stabilized or had improved CK levels and muscular and/or respiratory function following treatment with alglucosidase alfa \[[@CR63]\]. Furthermore, alglucosidase alfa was reported to be well tolerated, with most adverse events categorized as mild to moderate infusion-related reactions. ERT with alglucosidase alfa has been shown to increase life expectancy and survival in IOPD and LOPD \[[@CR5], [@CR64]\]. A key challenge in the MENA region is access to treatment and availablilty of alglucosidase alfa. Consensus recommendations {#Sec18} ------------------------- ### Initiation {#Sec19} After a diagnosis of Pompe disease by DBS screening and a confirmatory secondary test such as enzyme testing or genetic studies, treatment with alglucosidase alfa should be initiated depending on the status of the patient (Table [4](#Tab4){ref-type="table"}) \[[@CR6], [@CR7], [@CR65]\].Table 4Recommendations for initiation of alglucosidase alfa ERT based on patient statusPatient symptomatologyRecommendations for alglucosidase alfa ERTPresymptomatic with no signs or symptomsERT not necessary. Patient should be monitored every 6 months and ERT initiated if there is evidence of clinical deteriorationPresymptomatic with abnormal muscle imaging or abnormal muscle biopsyERT should be considered on a case-by-case basisSymptomatic with signs or symptomsERT should be initiated in patients with muscle weakness or reduced pulmonary functionPatients with markedly advanced disease, who have lost ambulation and are ventilation-dependentERT should be administered for 1 year with evaluation of effectivenessAdapted with permission from Cupler et al. Consensus treatment recommendations for late-onset Pompe disease. Muscle Nerve. 2012;45(3):319--33. \[[@CR6]\] © 2011 Wiley Periodicals, IncERT enzyme replacement therapy In presymptomatic patients with no signs or symptoms, ERT is not necessary. However these patients should be monitored every 6 months and treatment with alglucosidase alfa initiated if there is evidence of clinical deterioration in muscle or pulmonary function. Presymptomatic patients who have abnormal muscle imaging or muscle biopsy, and patients without clinical signs but with MRI abnormalities in muscles not traditionally tested (e.g. paraspinal muscles), should be considered for treatment with alglucosidase alfa on a case-by-case basis. ERT with alglucosidase alfa should be initiated in patients with symptoms or signs of Pompe disease, including early signs of muscle weakness or respiratory insufficiency. ERT should be considered irrespective of whether the patient is using noninvasive ventilation. In advanced patients with severe signs or symptoms, alglucosidase alfa should be administered for 1 year and the effectiveness of the treatment monitored. If patients display a stabilization or improvement in symptoms, ERT should continue. Continuation of ERT in other patients should be considered on a case-by-case basis. It should be noted that there are no randomized controlled trials to display efficacy of ERT in advanced patients, however there are some data in the literature showing some benefit in such patients. The recommended dosage of alglucosidase alfa is 20 mg/kg body weight administered every 2 weeks as an intravenous infusion \[[@CR66]\]. Total infusion volume is determined by patient body weight and should be administered over approximately 4 hrs. Infusion rates should be increased in a step-wise manner, with an initial infusion rate of 1 mg/kg/hr which can be increased by 2 mg/kg/hr every 30 mins until patient tolerance is established, up to a maximum rate of 7 mg/kg/hr. Anaphylaxis and severe allergic reactions have been observed in patients during, and up to 3 hrs after, alglucosidase alfa infusion. Therefore, it is important that appropriate medical support, including cardiopulmonary resuscitation equipment, is readily available during administration. In the event of anaphylaxis or other severe allergic reactions, immediate discontinuation of administration should be considered and appropriate medical treatment should be initiated. Patients should also be monitored for the development of systemic immune-mediated reactions involving skin and other organs while receiving alglucosidase alfa. Where it is appropriate and the facilities exist, the goal should be infusions at a local center. Transition of patients to home therapy after 6 months of therapy in an infusion center can be considered based on clinical judgment. This may not be appropriate in patients who have experienced adverse effects due to ERT. ### Monitoring {#Sec20} Patients with LOPD undergoing ERT with alglucosidase alfa should be clinically monitored every 6 months with the tests described below. Ideally the patients should be assessed by the same examiner at the same time of day (morning or afternoon) to decrease confounding variables. Also the patient should be encouraged to give their best effort. If the patient has experienced a recent intercurrent illness, the assessment should be postponed to allow sufficient recovery to baseline. #### Manual muscle testing {#Sec21} Manual muscle testing (MMT) should be performed to assess skeletal muscle strength using the Medical Research Council (MRC) grading scale (range 0--5) \[[@CR67]\]:0 No contraction1 Flicker or trace of contraction2 Active movement, with gravity eliminated3 Active movement against gravity4- Active movement against gravity and resistance to minimal pressure4 Active movement against gravity and resistance to moderate pressure4+ Active movement against gravity and resistance to strong pressure5 Normal power Muscle groups that should be assessed include: neck muscles, shoulder abduction, elbow flexion and extension, hip flexion and abduction, knee flexion and extension, and foot dorsal and plantar flexion. For consistency, this should be measured by the same examiner, either a physician or a physiotherapist. #### Quantitative muscle testing {#Sec22} Where available, quantitative muscle testing (QMT) should be performed using hand-held dynamometry (HHD) \[[@CR35], [@CR47]\]. The strength of muscle groups is measured in Newtons and maximum isometric contraction values are assessed with the break technique, in which the examiner applies adequate force to overcome the examinee, thereby producing an eccentric contraction. HHD values obtained for the different muscle groups are expressed as percentages of age- and sex-matched reference values (e.g. \[[@CR68]\]). #### Vital capacity {#Sec23} Around 60 % of LOPD patients have a mild reduction in vital capacity (\<80 % predicted) while 30--40 % have a moderate reduction (\<60 % predicted) \[[@CR52]\]. Screening for diaphragmatic involvement should be performed in the upright and supine positions using a hand-held spirometer. In healthy subjects, vital capacity is 5--10 % less in the supine than the upright position; a drop ≥10 % is suggestive of diaphragmatic weakness and a drop \>30 % is suggestive of severe diaphragmatic weakness \[[@CR53]\]. If diaphragmatic weakness is found, patients should be referred for formal pulmonary function testing (PFT) and possible sleep studies to assess for nocturnal apnea. Full PFTs should be performed where available including maximum inspiratory pressure (MIP) and maximum expiratory pressure (MEP) as they may be more sensitive to early respiratory muscle weakness \[[@CR52]\]. #### Six-minute walk test {#Sec24} The 6-min walk test (6MWT) is used for the objective evaluation of functional exercise capacity; the objective is for the patient to walk as far as possible in 6 mins. Detailed methods are available \[[@CR69]\], but briefly, the 6MWT should be performed indoors, along a flat, straight, quiet, corridor 30 m in length, with the length of the corridor marked every 3 m and the turnaround points marked with a cone. The starting line, which marks the beginning and end of each 60-m lap, should be marked on the floor. The patient walks the course back and forth and is permitted to slow down, stop and rest as necessary but encouraged to resume walking as soon as they are able. The healthcare practitioner should time the 6 mins, counting the laps to determine the distance covered, and record patient dyspnea and fatigue using the Borg scale pre- and post-test. #### Quality of life measurement {#Sec25} The Short Form 36 (SF36) Health Survey has been widely used as a QOL tool in patients with LOPD \[[@CR70]--[@CR72]\], with LOPD patients shown to have a markedly reduced QOL in the physical health domains and a slightly reduced QOL in the mental health domains when compared with the general population \[[@CR70]\]. The SF36 Health Survey has been translated and validated in both Arabic \[[@CR73]\] and Farsi \[[@CR74], [@CR75]\] languages. Ideally, more disease-specific tools (e.g. the IPA/Erasmus MC Pompe survey \[[@CR37]\]) would be used, however those have not been standardized or validated in Arabic or Farsi. #### Laboratory tests {#Sec26} In the first year post-diagnosis, laboratory tests should be performed every 3 months, followed by 6-monthly monitoring in the following years if stable on ERT (Table [5](#Tab5){ref-type="table"}).Table 5Summary of monitoring assessments to be made during ERTTestFrequencyManual muscle testingQuantitative muscle testingVital capacityEvery 6 monthsTime on ventilation daily (invasive or noninvasive)Six-minute walk testQuality of life measurementCreatine kinaseEvery 3 months in the first year post-diagnosisAlanine transaminaseAspartate transaminaseEvery 6 months if stable on ERTAntibody titersElectrocardiographyAt baseline and repeated regularly if clinically indicatedEchocardiographyDEXA (bone mineral density)Audiology assessmentDEXA dual-energy X-ray absorptiometry, ERT enzyme replacement therapy #### Creatine kinase {#Sec27} ERT therapy has been shown to stabilize or improve CK levels in LOPD patients and their reduction is considered a useful indicator of response to treatment \[[@CR63]\]. However, as CK levels can fluctuate, this may be an unreliable indicator unless a consistent and significant reduction is seen. #### GAA antibody titers {#Sec28} A number of factors have been identified as the cause of poor response to ERT, one of which is high, sustained antibody titers (HSAT) \[[@CR72]\]. However, while HSAT has been shown to correlate with poor response to ERT in IOPD \[[@CR76], [@CR77]\], knowledge of the role of antibodies in the LOPD population is limited. A recent study has shown that HSAT in a subset of LOPD patients is associated with clinical decline; however further studies are required to fully understand impact of antibodies in LOPD \[[@CR72]\]. #### Audiology assessment {#Sec29} While considered rare, there are reports of mild hearing loss in LOPD patients \[[@CR45], [@CR46]\]. It is therefore recommended that an audiology assessment is performed at baseline and then as clinically indicated. Algorithm for treatment of LOPD {#Sec30} ------------------------------- In asymptomatic patients with a confirmed diagnosis of Pompe disease, the experts recommended conducting PFTs and muscle strength tests; close monitoring for objective signs and symptoms every 6 months was also recommended (Table [5](#Tab5){ref-type="table"}). Upon onset of signs or symptoms, the experts recommended commencement of ERT with alglucosidase alfa (Fig. [5](#Fig5){ref-type="fig"}).Fig. 5Algorithm for treatment of LOPD. Abbreviations: ERT, enzyme replacement therapy; MRI, magnetic resonance imaging. \Restarting of ERT with alglucosidase alfa should be considered if there is rapid deterioration post-discontinuation ### Treatment failure {#Sec31} The experts defined treatment failure as objective and persistent deterioration of functions following 52 weeks of therapy. Evaluation should include physical examination, assessment for alternative etiologies of disease progression (e.g. hypothyroidism, vitamin D deficiency), laboratory studies, muscle MRI, GAA antibody titers, and possible muscle biopsy. In non-responders, treatment should be discontinued and progress monitored if an alternative explanation is not determined. Monitoring should be continued after ERT discontinuation. Restarting ERT should be considered if the rate of deterioration increases after discontinuation of ERT. Individualized therapeutic decisions such as high-dose ERT are at the discretion of the treating physician. Management of components of LOPD {#Sec32} ================================ Respiratory {#Sec33} ----------- ### Sleep study {#Sec34} A sleep study should be performed when there is an abnormal drop of \>10 % in FVC between the upright and supine position, or when there are symptoms suggestive of nocturnal hypoventilation or sleep apnea. If the sleep study demonstrates abnormalities then a pulmonologist with interest in neuromuscular disease should assess the patient for possible bi-level positive airway pressure (BPAP) or other noninvasive ventilator support to improve nocturnal respiration. Cardiac {#Sec35} ------- ### Electrocardiography {#Sec36} A study of the clinical spectrum of LOPD patients identified three subjects who suffered from arrhythmias due to Wolff--Parkinson--White syndrome despite no echocardiographic signs of cardiomyopathy \[[@CR1]\] and this should therefore be considered during cardiac monitoring of LOPD patients. Some patients may have short PR interval in their electrocardiogram (ECG) secondary to enhanced conduction \[[@CR42]\]. Others may have abnormalities reflecting their underlying cardiac disease (e.g. bundle branch block), rather than Pompe disease. As such, ECG should be performed at baseline, and repeated regularly only if clinically indicated. ### Echocardiography {#Sec37} Unlike patients with the infantile form, patients with LOPD do not typically develop hypertrophy of the left ventricle (LVH) \[[@CR37], [@CR42], [@CR78]\]. In a study of 75 adult patients with hypertrophic cardiomyopathy, none had genetic evidence of Pompe disease \[[@CR78]\]. Neither Hagemans et al. nor Soliman et al. found LVH in their series of adult patients with LOPD \[[@CR37], [@CR42]\]. Most of the cardiac abnormalities described in patients with LOPD are explained by concurrent underlying diseases, rather than LOPD \[[@CR42]\]. ECGs should be performed at baseline, then as clinically indicated. Gastrointestinal issues {#Sec38} ----------------------- ### Gastrointestinal motility dysfunction {#Sec39} A 2010 study reported gastrointestinal (GI) symptoms of chronic constipation and GI reflux in four out of six LOPD patients studied at a single institution \[[@CR44]\]. At 1 year follow-up, the patients reported a marked improvement of intestinal symptoms. Another study reported three LOPD patients with chronic diarrhea, postprandial bloating, and abdominal pain \[[@CR79]\]. Two of the patients reported fecal incontinence while the other reported synchronous vomiting and diarrhea; however all GI symptoms were reported to be resolved within the first 6 months of ERT. ### Swallowing dysfunction {#Sec40} A retrospective review of LOPD patients evaluated at the neuromuscular clinic at Duke University Medical Center identified 12 patients, three of whom had symptoms of oropharyngeal dysphagia \[[@CR41]\]. This was categorized as mild in two cases and severe in one, with the degree of swallowing impairment appearing to correlate with overall physical strength and function. Moderate or severe lingual weakness was found to be associated with dysphagia, and swallowing difficulties were generally more oral than pharyngeal in nature. It was concluded that screening for symptoms of dysphagia could help reduce morbidity and mortality, while improving understanding of the LOPD phenotype. A recent study has further demonstrated evidence of lingual weakness in LOPD, with a quantitative assessment showing lingual weakness in 80 % of the sample \[[@CR80]\]. Diet/Nutrition {#Sec41} -------------- At baseline, a study of 17 patients with LOPD undergoing ERT identified increased fat mass in five patients in severe disease stage despite normal body mass index (BMI) \[[@CR81]\]. Fat mass was found to correlate inversely, and lean mass directly, with CK, prealbumin, and albumin levels. ERT resulted in significant increases in BMI and fat mass, and a trend towards increased lean mass. Prealbumin and albumin levels increased as early as after the first months of ERT. This study highlighted that BMI may underestimate fat mass in patients in severe stage of disease, due to altered body composition. Furthermore, patients may have a relative protein malnutrition which is reversed by ERT, this reflecting restoration of normal muscle metabolic pathways. The increased BMI may indicate a reduction in energy consumption during exercise or respiration, along with clinical improvement. ### High protein diet {#Sec42} A high-protein diet has been shown to have beneficial effects in Pompe patients \[[@CR82]\]. A ventilator-dependent Pompe patient fed a general diet supplemented with branched-chain amino acids, which are the principal amino acids involved in muscle protein synthesis and utilization, showed improved respiratory function and muscle strength, resulting in daytime weaning form the ventilator. The potential advantages of a branched-chain amino acids-supplemented liquid diet over a high-protein diet include theoretical sparing of amino acids required for muscle protein synthesis by providing higher concentrations of postprandial branched-chain amino acids in the circulation, and better tolerance by a ventilator-dependent or debilitated patient. ### Supplements {#Sec43} Supplementation of LOPD patients with L-alanine reduces protein turnover and catabolism \[[@CR83]\]. A study of five subjects found that L-alanine supplementation decreased resting energy expenditure, leucine flux, and leucine oxidation to levels lower than those observed in control subjects. L-alanine has not been studied in combination with ERT. ### Gastrostomy tube {#Sec44} In patients where muscular weakness affects the ability to eat or where breathing problems interfere with eating, a gastrostomy tube (G-tube) may be necessary for providing adequate nutrition \[[@CR84]\]. These may also be used to improve nutrition in some patients who have normal swallowing function. Exercise {#Sec45} -------- An uncontrolled prospective study of 34 patients found that compliance to high-protein and low-carbohydrate nutrition and exercise therapy significantly slowed deterioration of muscle function as measured by the Walton scale, and improved the natural history of disease progression \[[@CR85]\]. Another study investigated the effect of exercise training on muscular strength and body composition in five patients with LOPD receiving ERT who underwent a 20-week program of supervised aerobic and progressive resistance exercise training. Exercise training resulted in a significant increase in muscular strength and 6-min walking distance despite no change in total and lower extremity lean body mass, highlighting the benefits of exercise training in patients with LOPD on ERT \[[@CR86]\]. Studies have also sought to investigate whether exercise training during ERT infusion increases effectiveness of therapy, however in a study of five LOPD patients following a 6-month period of exercise training, no significant functional changes in body composition, isometric strength, or 6-min walking distance were identified \[[@CR87]\]. Bone {#Sec46} ---- Low bone mineral density and osteoporosis have been reported in LOPD patients \[[@CR47]\]. Studies of the effect of ERT on bone mineral density suggest that ERT administration may moderately improve bone mineral density in some, but not all, LOPD patients \[[@CR88], [@CR89]\]. ### DEXA scan {#Sec47} Due to this bone mineral density component of LOPD, it is recommended that patients are screened at baseline with dual-energy X-ray absorptiometry (DEXA) and then as clinically indicated \[[@CR6], [@CR47], [@CR52]\]. ### Vitamin D plus calcium +/− bisphosphonates {#Sec48} Patients with abnormal DEXA z-scores should be supplemented with vitamin D and calcium \[[@CR47]\]. There is insufficient evidence to recommend bisphosphonates as a preventative therapy, however their use in LOPD patients should follow the same guidelines as for the general population \[[@CR6], [@CR52]\]. Others {#Sec49} ------ ### Possible increase in cerebral vascular anomalies {#Sec50} An investigation into cerebrovascular anomalies in six LOPD patients identified brain vascular anomalies, including dolichoectasia of the basilar artery and ectasia of internal carotids, in four out of the six patients \[[@CR44]\]. Two patients had clinical signs related to the arteriopathy, including partial paralysis of the third cranial nerve and transient ischemic attacks. ERT at 1 year follow-up was found to have no effect on the size of cerebral vessels and the study concluded that as intracranial artery abnormalities are not infrequent in patients with LOPD, they should be specifically investigated in the presence of unexplained CNS symptoms. A 2008 case report characterized the thrombotic complications of a basilar artery aneurysm in a young adult with Pompe disease, with the authors concluding that screening of intra-cerebral vessels to potentially diagnose thrombotic and thromboembolic complications may be considered in young adults with Pompe disease \[[@CR90]\]. A study published in 2011 reported five LOPD patients with aortic arteriopathy involving primarily the ascending thoracic aorta, highlighting that aneurysmal dilatation of the thoracic aorta is an underreported vascular complication of LOPD \[[@CR91]\]. The authors suggested that chest X-ray and echocardiography should be incorporated as initial screening tools for aortic aneurysms in patients with LOPD. Furthermore, contrast-mediated thoracic CT or MRI may be necessary when ectasia is suspected or the ascending aorta is not visualized. ### Genetic counseling {#Sec51} As Pompe is an inherited autosomal recessive disease, it is important to undertake genetic counseling with families that are known to be carriers or when there is diagnosis of a new case in a family. The most common inheritance scenario in Pompe disease is where both parents are asymptomatic carriers; in this instance the risk of Pompe disease is 1 in 4 (25 %), the risk that the child will become a carrier is 2 in 4 (50 %), and the risk that the child will be unaffected is 1 in 4 (25 %). As Pompe disease is an autosomal recessive disorder, typically counseling can be performed with an emphasis on prenatal testing and early diagnosis in the newborn. Pregnancy {#Sec52} --------- Pregnancies in Pompe disease patients, including cases of spinal anesthesia and Cesarean section, have been shown to result in the birth of healthy infants \[[@CR92]\], however the pregnancy should be considered high risk. In 2008 it was reported that a 31-year-old patient with known Pompe disease with symptoms and signs of respiratory dysfunction as well as preeclampsia underwent urgent Cesarean section under regional anesthesia, resulting in the birth of a healthy baby girl. There are limited data on the use of alglucosidase alfa in pregnant women; however studies in animals have shown reproductive toxicity \[[@CR93]\]. While safe continuation of ERT during pregnancy and lactation has been reported in a case study \[[@CR94]\], the potential risk for humans is unknown and the decision to use alglucosidase alfa during pregnancy needs to be made on an individual basis \[[@CR93]\]. A case study reported a primiparous 40-year-old woman diagnosed with Pompe disease whose clinical condition remained fairly stable until the 25th gestational week, after which problems with mobility and respiration were experienced. Fetal growth, as monitored by ultrasound, was reported to be normal and a healthy boy was born at a gestational age of 37 weeks and 5 days by elective Cesarean section. There were no maternal complications and the child developed normally. The mother's physical condition at 1 year post-partum was similar to prior to her pregnancy. Pharmacokinetic studies following enzyme infusion showed that alglucosidase alfa was secreted into the breast milk, with enzyme activity in the breast milk returning to the pre-infusion level after 24 hrs. Alglucosidase alfa may be excreted in breast milk and as there are limited data on the effects in neonates exposed to alglucosidase alfa via breast milk, cessation of breastfeeding during use of alglucosidase alfa should be advised \[[@CR93]\]. Future therapies for LOPD {#Sec53} ========================= NeoGAA {#Sec54} ------ NeoGAA has been designed to improve delivery of rhGAA to lysosomes by remodeling the carbohydrate moieties on the enzyme to exhibit a high-affinity ligand for the cation-independent mannose 6-phosphate receptor which is responsible for cellular uptake \[[@CR95]\]. In vivo* studies of administration to Pompe mice demonstrate improved clearance of glycogen from affected muscles when compared with the unmodified rhGAA, suggesting promise in enhancing the efficacy of ERT for Pompe disease \[[@CR95]\]. NeoGAA is currently undergoing Phase I clinical trials in humans to assess tolerability, pharmacokinetics, and pharmacodynamics \[[@CR96]\]. GAA fusion protein {#Sec55} ------------------ BMN 701 is a fusion protein of insulin-like growth factor and GAA which has a high affinity for the cation-independent mannose 6-phosphate receptor \[[@CR97]\]. BMN 701 has biochemical properties similar to rhGAA but is delivered more effectively to the lysosomes. In vivo studies have shown improved clearance of glycogen in Pompe mouse models and the therapy is now in Phase III trials \[[@CR97], [@CR98]\]. Chaperone therapy {#Sec56} ----------------- Chaperone therapy, also known as enzyme enhancement therapy (EET), is where pharmacological protein chaperones are co-administered with a protein therapy to improve efficacy. In vitro and in vivo studies show that co-administration of rhGAA and chaperones such as N-butyldeoxynojirimycin (NB-DNJ) \[[@CR99]\] or AT2220 (duvoglustat HCl) \[[@CR100]\] results in more efficient correction of enzyme activity, with improved delivery to lysosomes, enhanced enzyme maturation, increased enzyme stability, and greater glycogen reduction. A recently reported Phase II trial showed that co-administration of duvoglustat HCl and rhGAA to Pompe patients increased active plasma rhGAA AUC levels in all Pompe patients and that approximately 70 % of patients had increased muscle rhGAA activity \[[@CR101]\]. Chaperone therapy can also be given alone, with the idea that the chaperone will bind to the partially active molecule and traffic it to the lysosome where the acidic pH will dislodge the chaperone and permit the defective enzyme to work \[[@CR102]\]. Normally, defective enzymes are tagged for destruction, however the chaperone prevents their degradation. While Phase II trials of chaperone monotherapy have been initiated, they were subsequently discontinued \[[@CR103]\] due to safety concerns and the future of chaperone monotherapy remains unclear. Gene therapy {#Sec57} ------------ Adeno-associated virus (AAV)-mediated delivery of GAA has been shown to result in partial biochemical correction of the skeletal muscles and diaphragm and improved motor function in animal models of Pompe disease \[[@CR104], [@CR105]\]. Results from a Phase I/II study of AAV-GAA in a severely affected patient group of five children dependent on mechanical ventilation despite ERT suggest gene therapy may be safe and may lead to modest improvements in volitional ventilatory performance measures \[[@CR106]\]. Gene therapy led to significant increases in unassisted tidal volume, as well as an increase in patient tolerance for duration of unassisted breathing. However, further studies in larger, more diverse patient populations are required to understand the efficacy and safety of gene therapy in Pompe disease. Discussion {#Sec58} ========== This consensus manuscript is the first to provide region-specific guidelines for the MENA region on the diagnosis and treatment of LOPD. They take into account the challenges that are unique to the region; namely delayed diagnosis, access to diagnostic tools, and access to treatment. Considering that the prevalence of LOPD in the region is at least as high as in other countries, and is likely to be higher, the publication of regional guidelines serves to facilitate the prompt diagnosis, appropriate treatment, and proper monitoring that will improve survival and patient outcomes. There is a lack of awareness of LOPD in the region, which potentially leads to missed cases, delayed diagnosis, and delayed treatment. There is therefore a need to improve the knowledge of physicians and adult neurologists so that they are aware of LOPD as a potential differential diagnosis in patients presenting with limb--girdle disease. Another challenge faced within the region is the lack of patient education. The authors are aware that there is a reluctance of patients to seek medical attention in the early stages of the disease, which leads to delayed diagnosis and treatment and poor patient outcomes. This is potentially associated with disease stigma and denial of the disease, which also result in a lack of discussion within families and a missed opportunity for family screening. Another patient challenge in the region is the refusal of lifelong treatment or non-compliance with physician recommendations, especially if the disease is mild in severity. Patients need to be educated to be aware of the disease and the need to seek prompt medical attention. The authors hope that dissemination of these guidelines will assist healthcare professionals in achieving prompt diagnosis, appropriate treatment, and proper follow-up of LOPD patients in order to reduce the burden of the disease. 6MWT : 6-minute walk test AAV : Adeno-associated virus ALT : Alanine aminotransferase AMD : Acid maltase deficiency AST : Asparate aminotransferase BMI : Body mass index BPAP : Bi-level positive airway pressure CHO : Chinese hamster ovary CK : Creatine kinase DBS : Dried blood spot DEXA : Dual-energy X-ray absorptiometry ECG : Electrocardiogram EET : Enzyme enhancement therapy EMG : Electromyograph ERT : Enzyme replacement therapy FVC : Forced vital capacity GAA : Acid alpha-glucosidase GI : Gastrointestinal GSDII : Glycogen storage disease type II HHD : Hand-held dynamometry HSAT : High, sustained antibody titer IOPD : Infantile-onset Pompe disease LDH : Lactate dehydrogenase LOPD : Late-onset Pompe disease LOTS : Late-Onset Treatment Study LVH : Left ventricular function MENA : Middle East and North Africa MGA : Maltase gluco-amylase MMT : Manual muscle testing MRC : Medical Research Council MRI : Magnetic resonance imaging PFT : Pulmonary function test QMT : Quantitative muscle testing QOL : Quality of life rhGAA : Recombinant human GAA RSS : Rigid spine syndrome SF36 : Short Form 36. Competing interests All authors received honoraria and support to travel to the consensus paper working group meeting at which the consensus recommendations presented in this manuscript were discussed. Dr Nouriya Al-Sanna'a, Dr Fawziah Al-Sharif, Dr Saeed Bohlega, Dr Mohamed Hamdan, Dr Nawal Makhseed, Dr Yalda Nilipour, Dr Nuri Shembesh, Dr Rawda Sunbul, Dr Seyed Hassan Tonekaboni, Dr Shahriar Nafissi, Dr Laila Selim and Dr Fatimah Alqarni have nothing to declare. Dr Edward Cupler reports receiving honoraria and consulting fees from Genzyme and Novartis and research support from Merck Serono. Dr Waseem Fathalla reports receiving consultancy fees from Genzyme, Shire and Biomarin. Dr Fatma Al Jasmi reports receiving honoraria for lectures, board membership, consultancy fees and grants from Genzyme, Shire, BioMarine, Orphan Europe and Sobi. Dr Mohammed Al Jumah reports receiving consultancy fees from Genzyme, Merck Serono, Novartis, Biogen and Bayer. Authors' contributions All authors contributed extensively to the work presented in this manuscript. EJC was the chairperson of the Pompe Middle East and North Africa Working Group and led the overall development of the manuscript, in addition to providing expert opinion on treatment strategies for management of Pompe disease. NAS reviewed the pathophysiology. SB addressed the epidemiology and genetic basis of Pompe disease and led the consensus discussion on diagnosis of Pompe disease. WF and FA covered the clinical presentation of infantile-onset and late-onset Pompe disease, respectively. MAH reviewed the cardiac issues related to Pompe disease and ERT. MAJ led the consensus discussion on treatment of late-onset Pompe disease and provided updates on the diagnostic approaches along with RS. YN provided expert opinion on muscle pathology in Pompe disease. SHT led the consensus discussion on treatment of infantile onset Pompe disease and also addressed enzyme replacement therapy in infantile and late-onset Pompe disease. FAJ, NM, FAS, SN, NS, and LS presented their experience in management of Pompe disease in their country and outlined the local challenges to optimal management. All authors read and approved the final manuscript. Medical writing support in the development of this manuscript was provided by Dr Marcus Corander of Choice Healthcare Solutions, and funded by Genzyme, a Sanofi Company. Genzyme reviewed the manuscript and provided comments for author consideration. The authors would like to thank Dr Dina El-Shafei of Genzyme for her initiation and support of the MENA Working Group that facilitated the process of the guideline manuscript development.	{ "pile_set_name": "PubMed Central" }
Opinions of the United 2007 Decisions States Court of Appeals for the Third Circuit 8-24-2007 Curley v. Klem Precedential or Non-Precedential: Precedential Docket No. 05-4701 Follow this and additional works at: http://digitalcommons.law.villanova.edu/thirdcircuit_2007 Recommended Citation "Curley v. Klem" (2007). 2007 Decisions. Paper 490. http://digitalcommons.law.villanova.edu/thirdcircuit_2007/490 This decision is brought to you for free and open access by the Opinions of the United States Court of Appeals for the Third Circuit at Villanova University School of Law Digital Repository. It has been accepted for inclusion in 2007 Decisions by an authorized administrator of Villanova University School of Law Digital Repository. For more information, please contact Benjamin.Carlson@law.villanova.edu. PRECEDENTIAL UNITED STATES COURT OF APPEALS FOR THE THIRD CIRCUIT _______________ No. 05-4701 _______________ CORVET CURLEY; ELAINE CURLEY v. RONALD KLEM, a Police Officer, SUED IN HIS INDIVIDUAL CAPACITY; JOHN DOE; BILL DOE, two currently unknown Police Officers also sued in their individual capacities Corvet Curley, Appellant _______________ On Appeal from the United States District Court for the District of New Jersey (D.C. No. 98-cv-05256) District Judge: Honorable Katharine S. Hayden _______________ Argued March 27, 2007 Before: FISHER, JORDAN and ROTH, Circuit Judges (Filed: August 24, 2007) _______________ David S. Gould [ARGUED] Steven L. Salzman Richard L. Huffman David S. Gould, P.C. 61 Broadway - Suite 2820 New York, NY 10006 Counsel for Appellant Jeffrey M. Kadish, Esq. [ARGUED] Morgan Melhuish Abrutyn 651 West Mount Pleasant Avenue - # 200 Livingston, NJ 07039-1673 Counsel for Appellees _______________ OPINION OF THE COURT _______________ JORDAN, Circuit Judge. This civil rights suit, after a long and difficult history, is before us for the second time. Plaintiff Corvet Curley (“Curley”), an officer with the Port Authority of New York 2 and New Jersey, and his wife, Elaine, sued defendant Ronald Klem (“Klem”), a New Jersey State Trooper, under 42 U.S.C. § 1983, alleging that Klem violated Curley’s constitutional rights by shooting him while both Curley and Klem were responding to a police emergency at the George Washington Bridge. The Curleys appeal from a judgment order of the United States District Court for the District of New Jersey, entered after a jury trial. The jury made various findings of fact through special interrogatories, and stated by a verdict sheet its conclusion that Trooper Klem had not acted unreasonably under the circumstances. Based on those findings, the District Court entered judgment in favor of Klem on the basis of qualified immunity. For the reasons that follow, we will affirm, albeit on different grounds. I. A. Factual Background On the evening of November 20, 1997, at approximately 8:45 p.m., Trooper Klem was on duty and learned that a suspect, Deon Bailey (“Bailey”), had shot and killed a Long Branch police officer and stolen a police car. A follow-up radio transmission informed Klem that Bailey was on the Garden State Parkway and had fired shots at a another police car. Shortly after 9:00 p.m., Klem received another transmission, this one saying that Bailey was now in a green Toyota Camry he had stolen from a woman at a gas station. A few minutes later, a further radio transmission described 3 Bailey as a “tall, black male”1 and stated that he was headed north in the Camry on the New Jersey Turnpike. Klem and several other troopers found Bailey on the Turnpike and began chasing him, while Bailey shot at them. One of the troopers in the chase was shot in the arm, and Klem’s windshield was struck by a bullet. During the chase, Klem ended up as the nearest trooper behind Bailey. He followed Bailey to the toll plaza at the George Washington Bridge, where, according to his testimony, he briefly lost sight of the Camry. He then saw the Camry stopped on the far left side of the plaza. Klem stopped his car about thirty yards back, and approached the Camry at a jog. He testified that he was unaware of any other police officers on the scene at that time, and that he did not wait for back-up. Klem did not know that Bailey, upon arriving at the toll plaza, had crashed the Camry at high speed into a Nissan Pathfinder that was waiting in a toll lane. The crash sent the Pathfinder spinning out into the toll plaza some thirty feet from where the Camry had stopped. Immediately after the crash, Bailey shot himself in the head. According to a toll 1 At the summary judgment stage of the case, Klem claimed that the radio transmission described Bailey as a “thin, black male” rather than a “tall, black male.” See Curley v. Klem, 298 F.3d 271, 274 (3d Cir. 2002) (“Curley I”). However, at trial, Klem stated that the transmission had described the suspect as a “tall black male” and that he had misheard it as “thin black male.” 4 booth attendant and another law enforcement officer, Bailey was sprawled across the passenger seat of the Camry. The toll booth attendant stated that he had no trouble seeing the body. That same attendant next saw the two principal parties in this dispute, Curley and Klem, approaching the ill-fated scene. Curley was on duty that evening at the bridge. He was in his Port Authority police uniform, although not wearing his hat. He too had received a radio transmission stating that a black male in a stolen vehicle was being pursued by the New Jersey State Police, and was heading toward the bridge. By now it was nearing 9:30 p.m. Curley went to the New York side of the toll plaza in his marked police car, with both the lights and sirens on. After reaching the plaza, he turned his sirens off but left the lights on. He then saw a vehicle, which he later learned was the stolen Camry, headed toward the toll plaza at a high rate of speed, and he heard it crash into the Pathfinder. Curley drove his car toward the Pathfinder and stopped next to it. He looked over at the Camry, but had trouble seeing inside of it because the front end was smashed. He unholstered his gun, told the driver of the Pathfinder to stay in his vehicle, and moved toward the Camry. Curley testified that, at this point, he had his gun pointed toward the Camry. Realizing that he did not have cover, Curley pointed his gun at the ground, turned and began to move back toward his own car. 5 At approximately the same time that Curley was investigating the scene, Klem approached the back of the Camry with a shotgun in hand. He saw a toll collector pointing toward the center of the toll plaza. Klem testified that he had not heard any shots, and that all of the doors on the Camry were closed. Klem approached the Camry from the back right, and stopped by the right front passenger door, close enough to the Camry to be able to touch it. He testified that, as he approached the Camry, he looked into the rear seat of the vehicle and into the front seat of the vehicle; he testified that the air bags had deployed, and that the interior of the Camry was filled with dust from the air bags. Klem stated that, at that time, he did not see a body in the Camry and did not see blood on the air bags or seat. Klem turned in the direction that the toll collector had been pointing and saw a black male with a gun in his hand. According to Klem, the man had both hands on the gun and was pointing it directly at him. Klem testified that he shouted three times for the man with the gun, who was, in reality, Curley, to drop his gun. He also testified that Curley raised and lowered his gun to point at Klem three times while backpedaling away from Klem. Klem hesitated briefly, then fired his shotgun,2 hitting Curley in the leg. Immediately after he fired, someone screamed to him that he had just shot a cop. Klem then looked into the Camry and saw Bailey’s body. 2 At his deposition, Klem testified that about thirty seconds passed between the time he first saw Curley and the time he fired his shotgun. At trial, he testified that only ten to fifteen seconds had passed. 6 Klem testified that, had he earlier seen the body in the Camry, he never would have shot Curley.3 Curley testified that he never saw Klem and that he never heard anyone tell him to drop his gun. B. Procedural Background Curley filed suit under 42 U.S.C. § 1983, alleging that Klem used excessive force against him, in violation of the Fourth Amendment.4 Curley’s wife joined in the complaint, alleging loss of consortium. After discovery, the District Court granted summary judgment in favor of Klem. It held that Klem’s conduct was objectively reasonable and that he was thus shielded by qualified immunity. See Curley I, 298 3 It is undisputed that Bailey had been alone, and that Klem knew that. 4 “To state a claim for excessive force as an unreasonable seizure under the Fourth Amendment, a plaintiff must show that a ‘seizure’ occurred and that it was unreasonable.” Abraham v. Raso, 183 F.3d 279, 288 (3d Cir. 1999) (citing Brower v. County of Inyo, 489 U.S. 593, 599 (1989)). An officer seizes a person whenever he “restrains the freedom of a person to walk away[.]” Tennessee v. Garner, 471 U.S. 1, 7 (1985). Thus, there is “no question” that a shooting constitutes a seizure under the Fourth Amendment. Id. (“[T]here can be no question that apprehension by the use of deadly force is a seizure subject to the reasonableness requirement of the Fourth Amendment.”). The question that remains is whether the shooting was reasonable. 7 F.3d at 276 (recounting procedural history). Curley appealed, and we reversed the summary judgment. See id. at 273-74. In that opinion, we analyzed both the question of whether Klem’s conduct had violated Curley’s constitutional rights, and whether Klem was entitled to qualified immunity. We did so recognizing – indeed we reiterated it no less than four times in different ways – that, because we were reviewing a decision on a summary judgment motion, we were required to take the facts as Curley, the non-movant, had alleged them and to view every fact and inference in the light most favorable to Curley. See id. at 276-77; 279-80; 282-83. Given that procedural perspective, we determined that Klem’s actions would constitute an unreasonable seizure. Id. at 280. Next, we decided that, in the District Court’s qualified immunity analysis, the Court had not recognized factual disputes that precluded a grant of summary judgment. Id. at 281. Specifically, we noted that a number of facts, including whether Klem looked inside the Camry and how Curley behaved during the confrontation between him and Klem, were disputed and required resolution by a jury. Id. at 281- 83. Thus, we remanded the case to the District Court for resolution of the disputed facts by a jury. Id. at 283. On remand, the District Court held a jury trial and submitted both special interrogatories and a liability verdict sheet to the jury. In answer to the special interrogatories, the jury found that, when Klem approached the Camry, Bailey’s body was on the front seat of the car, not on the floorboards, and that Klem did not look into the window of the car. Furthermore, the jury found that Bailey’s body should have 8 been visible to someone standing in Klem’s position but that Klem had not made an objectively reasonable effort to look into the Camry. The jury also found that it was objectively reasonable for Klem to believe that the toll collector was signaling to the center of the plaza. Additionally, the jury found that Curley did not repeatedly point his gun at Klem, and that, when Curley was shot, he was not raising his gun to point it at Klem. Finally, the jury could not reach a unanimous decision and so did not answer whether Curley’s police uniform was visible to someone in Klem’s position or whether it was reasonable for Klem to believe that Curley was in civilian clothing. In addition to the special interrogatories, the District Court submitted to the jury a liability verdict sheet asking whether Klem’s conduct was objectively reasonable. See Curley v. Klem, 2006 WL 414093, at 2 (D.N.J. Feb. 21, 2006) (“Post-trial Opinion”). More precisely, the liability verdict sheet contained four questions, three of which the jury answered. Question One asked the jury whether “Trooper Ron Klem’s failure to act in an objectively reasonable manner in observing the Camry prevent[ed] him from seeing the perpetrator’s body in the Camry?” Question Two asked “Did Trooper Ron Klem act in an objectively reasonable manner in shooting Officer Curley during the confrontation?” Question Three asked “Was Trooper Ron Klem’s mistake in firing his weapon objectively reasonable?” The fourth question, left unanswered by the jury, asked whether “the plaintiff suffer[ed] damages that were proximately caused by Trooper Ron Klem’s conduct?” 9 The jury answered yes to Question One, thus finding that Klem’s failure to look in the Camry was not objectively reasonable. However, the jury also found, in response to Question Two, that Klem did act in an objectively reasonable manner during the confrontation with Curley. Finally, in response to Question Three, the jury found that Klem’s mistake in firing his weapon was objectively reasonable. Based on these findings, and with no separate analysis, the District Court entered judgment for Klem, stating that Klem was entitled to qualified immunity based on the jury’s answer to Question Three, and also noting the jury’s answer to Question Two. Curley moved for judgment as a matter of law or a new 5 trial. In its opinion addressing those post-trial motions, the District Court stated that the parties had agreed early in the case “that the jury would decide the issue of qualified immunity, and not the Court.” Id. at 4. On appeal, however, Curley points to several places in the record where he objected to the inclusion of Question Three on the liability verdict sheet and where he argued that a determination of qualified immunity was a question of law for the Court, not the jury. See Joint Appendix at A125 (“A jury can contribute fact finding to a qualified immunity question but not law finding”); Trial Transcript at T113 (“[Counsel for Klem] wants the jury to decide objectionable [sic] reasonableness 5 For purposes of the following discussion, when we speak of Officer Curley taking certain legal positions, it should be understood that his wife and co-plaintiff has also taken those positions. 10 and then to decide whether there was a violation of the state of the law. Which you called the second prong on qualified immunity. And what is very clear is that no case ever did or could submit that to the jury.”). Whether the District Court misunderstood Curley’s position or Curley failed to make it clear during the framing of the special interrogatories and the verdict sheet, the objective reasonableness of Klem’s actions was put to the jury. In support of his post-trial motions, Curley argued that the jury’s general liability verdict was not supported by the facts the jury had found in the special interrogatories and that the verdict should therefore be overridden. He also argued that the verdict could not stand because it was internally inconsistent, since it faulted Klem’s action in not looking in the Camry and yet stated that Klem’s behavior, including the mistaken shooting, was reasonable. The District Court found that the jury’s verdict was not inconsistent, and that the facts found by the jury in the special interrogatories did not warrant overturning the jury’s verdict for Klem. Post-trial Opinion, 2006 WL 414093, at 2-5. The District Court reasoned that Curley was attempting to reduce the case “down to a handful of seconds in the continuum of events.” Id. at 2. Rejecting that effort, the District Court found that the relevant events spanned a lengthy period, beginning at the time that Klem received the first radio transmission about Bailey. Id. Thus, the Court stated, although 11 those seconds discussed by the Third Circuit are important, still they were singled out not because they were “the case,” but because this [District] Court erroneously saw them as unfolding only one way. That the jury decided otherwise, that it viewed some of the preshooting events contrary to Trooper Klem’s account, does not necessarily drive a determination that he acted unreasonably when he mistakenly shot Officer Curley. Id. The District Court therefore found that there was no inconsistency or tension between the jury’s answers to the Special Interrogatories and its answers on the Liability Verdict Sheet. Id. Characterizing Questions One and Two as “General Liability” questions, the District Court held that those questions did not present alternative theories of liability. Id. at 5. The Court also held that the jury had decided in Question Three that Klem was entitled to qualified immunity. Id. at 3-5. Accordingly, the Court denied Curley’s motion for judgment as a matter of law or a new trial. Id. at 5. Curley then filed this appeal. He raises five questions, some of which are conceptually overlapping: (1) Whether the District Court erred in putting to the jury the question of the objective reasonableness of Klem’s mistake in shooting Curley; (2) Whether the District Court erred in refusing to treat the jury’s answers to special interrogatories as requiring a verdict for Curley; (3) Whether the District Court likewise erred in refusing to treat the jury’s answer to the first question on the verdict sheet, which dealt with Klem’s failure to see 12 Bailey’s body in the Camry, as requiring a verdict for Curley (Curley calls this his “first theory of liability”); (4) Whether the District Court erred in refusing to enter a verdict for Curley or to order a new trial based on Klem’s actions in the confrontation and shooting (Curley’s “liability theory number two”); and (5) Whether the District Court erred in refusing to treat Curley’s two liability theories as alternatives that necessitated a verdict for Curley if the jury agreed with either. II. The District Court had jurisdiction over this case under 28 U.S.C. §§ 1331 and 1343, and entered final judgment on September 29, 2005. This Court has jurisdiction over final judgments of the District Court under 28 U.S.C. § 1291. The standard of review for a motion for judgment as a matter of law is plenary. Lightning Lube, Inc. v. Witco Corp., 4 F.3d 1153, 1166 (3d Cir. 1993) (“We exercise plenary review of an order granting or denying a motion for judgment as a matter of law and apply the same standard as the district court.”). The standard of review on a motion for a new trial is “abuse of discretion unless the court’s denial of the motion is based on application of a legal precept, in which case our review is plenary.” Honeywell, Inc. v. American Standards Testing Bureau, Inc., 851 F.2d 652, 655 (3d Cir. 1988). 13 III. A. The Saucier Test for Qualified Immunity As we noted in Curley I, the claim here arises under 42 U.S.C. § 1983, which “provides a cause of action for any person who has been deprived of rights secured by the Constitution or laws of the United States by a person acting under color of law.” 298 F.3d at 277. Police officers, embodying the authority of the state, are liable under § 1983 when they violate someone’s constitutional rights, unless they are protected by qualified immunity. Qualified immunity is “the best attainable accommodation of competing values ... .” Harlow v. Fitzgerald, 457 U.S. 800, 814 (1982). Since public officials exercising discretionary powers may sometimes abuse their discretion, the immunity is qualified, rather than absolute, so that civil damages can serve as a restraint. At the same time, the immunity incorporates a recognition that “claims frequently run against the innocent as well as the guilty – at a cost not only to the defendant officials, but to society as a whole.” Id. While unproductive societal costs may be unavoidable in a system that relies on private litigation as one means to enforce our constitutional norms, the aim of qualified immunity is to limit those costs to the greatest practical degree. We do not want to let the threat of litigation and personal liability “deter[] ... able citizens from acceptance of public office[,]” nor do we want to “dampen the ardor of all but the most resolute, or the most irresponsible public officials, in the unflinching discharge of their duties.” Id. (internal quotation marks, brackets, and citation omitted). Hence, “[t]his immunity is broad in scope and protects ‘all but 14 the plainly incompetent or those who knowingly violate the law.’” Couden v. Duffy, 446 F.3d 483, 501 (3d Cir. 2006) (Weis, J., dissenting) (quoting Malley v. Briggs, 475 U.S. 335, 341 (1986)). In Saucier v. Katz, 533 U.S. 194 (2001), the Supreme Court articulated a two step test for determining whether a government official, such as a police officer, is entitled to qualified immunity.6 In the first step, a court must address whether “the officer’s conduct violated a constitutional right[.]” Id. at 201. In an excessive force case, whether there is a constitutional violation is “properly analyzed under the Fourth Amendment’s ‘objective reasonableness’ standard[.]” Graham v. Connor, 490 U.S. 386, 388 (1989). The relevant inquiry is “the reasonableness of the officer’s belief as to the appropriate level of force[,]” which “should be judged from [the officer’s] on-scene perspective,” and not in the “20/20 vision of hindsight.” Saucier, 533 U.S. at 205 (internal citations and quotation marks removed). 6 Saucier was not the first time the Court had framed the analysis in two parts, see Siegert v. Gilley, 500 U.S. 226, 232 (1991) (“A necessary concomitant to the determination of whether the constitutional right asserted by a plaintiff is ‘clearly established’ at the time the defendant acted is the determination of whether the plaintiff has asserted a violation of a constitutional right at all.”), but it is the decision that has become synonymous with the current approach to qualified immunity analysis. 15 That reasonableness inquiry requires “careful attention to the facts and circumstances of each particular case, including the severity of the crime at issue, whether the suspect poses an immediate threat to the safety of the officers or others, and whether he is actively resisting arrest or attempting to evade arrest by flight.” Graham, 490 U.S. at 396. The analysis “requires a careful balancing of the nature and quality of the intrusion on the individual’s Fourth Amendment interests against the countervailing governmental interests at stake.” Id. (citations and internal quotation marks omitted). The balancing must be conducted in light of the facts that were available to the officer. See Maryland v. Garrison, 480 U.S. 79, 85 (1987) (“[W]e must judge the constitutionality of [the officers’] conduct in light of the information available to them at the time they acted.”). It is, in other words, a “totality of the circumstances” analysis. See Curley I, 298 F.3d at 279 (assessing objective reasonableness of defendant’s actions on basis of totality of the circumstances); cf. Graham, 490 U.S. at 396 (proper application of reasonableness test used to analyze a claimed violation of Fourth Amendment right against unreasonable seizure “requires careful attention to the facts and circumstances of each particular case”); Abraham, 183 F.3d at 289 (“How much force is permissible to effectuate an arrest ... is determined based on the ‘totality of the circumstances.’”). “If, and only if, the court finds a violation of a constitutional right,” Scott v. Harris, 127 S. Ct. 1769, 1774 (2007), the court moves to the second step of the analysis and asks whether immunity should nevertheless shield the officer 16 from liability.7 The question at this second step is whether the right that was violated was clearly established, or, in other words, “whether it would be clear to a reasonable officer that his conduct was unlawful in the situation he confronted.” Saucier, 533 U.S. at 202. The Court explained that, again, “this inquiry ... must be undertaken in light of the specific context of the case, not as a broad general proposition.” Id. at 201. The Court went on to emphasize that even where reasonableness is a part of the inquiry for both the constitutional question and for qualified immunity, as it is in an excessive force case, the inquiries remain distinct. Id. at 204-05. “The concern of the immunity inquiry is to acknowledge that reasonable mistakes can be made as to the legal constraints on particular police conduct.” Id. at 205. Thus, the first step of the analysis addresses whether the force used by the officer was excessive, and therefore violative of the plaintiff’s constitutional rights, or whether it was reasonable in light of the facts and circumstances available to the officer at the time. This is not a question of immunity at all, but is instead the underlying question of whether there is even a wrong to be addressed in an analysis of immunity. The second step is the immunity analysis and addresses whether, if there was a wrong, such as the use of excessive force, the officer made a reasonable mistake about the legal constraints on his actions and should therefore be protected against suit 7 As further explained herein, infra at sections IV.B and IV.C, we do not have occasion to reach that second step here, because no constitutional violation occurred in this case. 17 While the Saucier analytical approach has been criticized for being unduly rigid and demanding resolution of constitutional issues when cases could be more simply disposed of on other grounds, see, e.g., Los Angeles County, California v. Rettele, 127 S. Ct. 1989, 1994 (2007) (Stevens, J., dissenting) (discussing the “unwise practice of deciding constitutional questions in advance of the necessity for doing so.”); Scott, 127 S. Ct. at 1774 n.4 (recounting criticisms of Saucier); P. Leval, Judging Under the Constitution, 81 NYU L. Rev. 1249, 1275-81 (2006) (describing Saucier as requiring courts to engage in “a puzzling misadventure in constitutional dictum”), its order of inquiry nevertheless remains mandatory. Scott, 127 S. Ct. at 1774 n.4 (declining to “address the wisdom of Saucier”). B. Evolving Approaches to Applying the Test The length of the foregoing review notwithstanding, the two-step Saucier test can be stated simply. Its application, however, presents perplexing logical and practical problems. The point of immunity is to protect someone from the burden imposed by litigation itself. It is supposed to be “an immunity from suit rather than a mere defense to liability ... .” Mitchell v. Forsyth, 472 U.S. 511, 526 (1985) (original emphasis). Hence, the Supreme Court has instructed that “[i]mmunity ordinarily should be decided by the court long before trial.” Hunter v. Bryant, 502 U.S. 224, 228, (1991). That is well and good when there are no factual issues in a case, but often the facts are intensely disputed, and our precedent makes clear that such disputes must be resolved by a jury after a trial. E.g., Estate of Smith v. Marasco, 430 F.3d 140, 152-53 (3d 18 Cir. 2005); Curley I, 298 F.3d at 278; Reitz v. County of Bucks, 125 F.3d 139, 147 (3d Cir. 1997). As a practical matter, then, in such cases the immunity becomes no more than a mere defense, Sloman v. Tadlock, 21 F.3d 1462, 1468 n.6 (9th Cir. 1994), and a sometimes challenging one to establish at that. The fundamental challenge lies in the nature of the questions that compose the test. Since they are mixed questions of law and fact, one is left to ask who should answer them. As we noted in Curley I, “[a] disparity of opinion exists among our sister circuits as to whether a judge or jury should make the ultimate immunity determination.” 298 F.3d at 278 n.3. The First, Fourth, Seventh, and Eleventh Circuits have all indicated that qualified immunity is a question of law reserved for the court.8 The Fifth, Sixth, 8 See Rodriguez-Marin v. Rivera-Gonzalez, 438 F.3d 72, 83 (1st Cir. 2006) (“While preliminary factual questions regarding qualified immunity are sent to the jury, the legal question of the availability of qualified immunity is ultimately committed to the court’s judgment.”) (internal quotation marks omitted); Willingham v. Crooke, 412 F.3d 553, 560 (4th Cir. 2005) (“The issue having now come before us, we hold that the legal question of a defendant’s entitlement to qualified immunity under a particular set of facts should be decided by the court, not by the jury.”); Riccardo v. Rausch, 375 F.3d 521, 526 (7th Cir. 2004) (“Immunity, however, is a matter of law for the court, to be decided without deference to the jury’s resolution-and preferably before the case goes to the jury.”); Johnson v. Breeden, 280 F.3d 1308, 1318 (11th 19 Ninth, and Tenth Circuits have permitted the question to go to juries.9 Precedent from the Second and Eighth Circuits can be Cir. 2002) (“When the case goes to trial, the jury itself decides the issues of historical fact that are determinative of the qualified immunity defense, but the jury does not apply the law relating to qualified immunity to those historical facts it finds; that is the court’s duty.”). 9 See McCoy v. Hernandez, 203 F.3d 371, 376 (5th Cir. 2000) (“while qualified immunity ordinarily should be decided by the court long before trial, if the issue is not decided until trial the defense goes to the jury which must then determine the objective legal reasonableness of the officers’ conduct.”); Champion v. Outlook Nashville, Inc., 380 F.3d 893, 900 (6th Cir. 2004) (“The issue of whether qualified immunity is applicable to an official’s actions is a question of law. However, where the legal question of qualified immunity turns upon which version of the facts one accepts, the jury, not the judge, must determine liability.”) (internal citations and quotation marks omitted); Ortega v. O’Connor, 146 F.3d 1149, 1156 (9th Cir. 1998) (finding no error in “the district court’s ‘extra’ reasonableness test, which ... constituted an appropriate and proper instruction to the jury on the second prong of the defendants’ qualified immunity defense-whether a reasonable state official could have believed his conduct was lawful-the prong as to which the existence of factual disputes requires the jury’s determination.”); Maestas v. Lujan, 351 F.3d 1001, 1010 (10th Cir. 2003) (“In short, the disputed issues of material fact concerning the objective reasonableness of Mr. Lujan’s 20 viewed as being on both sides of the issue, with the evolution being toward reserving the question for the court.10 actions are dispositive of the qualified immunity issue. Further, as stated above, Mr. Lujan retained the defense of immunity from liability even though the jury was needed to resolve issues of objective legal reasonableness. Therefore, the district court properly presented the reasonableness element of the qualified immunity analysis to the jury.”). 10 Compare Stephenson v. Doe, 332 F.3d 68, 81 (2d Cir. 2003) (“We believe that use of special interrogatories in this case resolves the difficulty of requiring the jury to decide ‘what the facts were that the officer faced or perceived’ and requiring the court to make the ultimate legal determination of whether qualified immunity attaches on those facts.”) with Oliveira v. Mayer, 23 F.3d 642, 650 (2d Cir. 1994) (“The District Court should have let the jury (a) resolve these factual disputes and (b) based on its findings, decide whether it was objectively reasonable for the defendants to believe that they were acting within the bounds of the law when they detained the plaintiffs.”); see also Kerman v. City of New York, 374 F.3d 93, 109 (2d Cir. 2004) (discussing roles of judge and jury in qualified immunity analysis, and citing both Stephenson and Oliveira). Compare Littrell v. Franklin, 388 F.3d 578, 585 (8th Cir. 2004) (“Where, as in this case, factual questions prevent a district court from ruling on the issue of qualified immunity, it is appropriate to tailor special interrogatories specific to the facts of the case. This practice allows the jury to make any requisite factual findings that the district court may then rely upon to make its own qualified 21 Our precedents too have evolved. Our recent precedents say that the court, not a jury, should decide whether there is immunity in any given case. E.g., Harvey v. Plains Twp. Police Dept., 421 F.3d 185, 194 n.12 (3d Cir. 2005); Carswell v. Borough of Homestead, 381 F.3d 235, 242 (3d Cir. 2004); Doe v. Groody, 361 F.3d 232, 238 (3d Cir. 2004). But that was not always our counsel. We had previously permitted the jury to answer the key immunity question of whether the challenged behavior of a government official was objectively reasonable. In Sharrar v. Felsing, 128 F.3d 810, 830-31 (3d Cir. 1997), we referred with approval to our earlier decision in Karnes v. Skrutski, 62 F.3d 485 (3d Cir. 1995), characterizing it as holding that, “a factual dispute relating to qualified immunity must be sent to the jury, and suggest[ing] that, at the same time, the jury would decide the issue of objective reasonableness.” Sharrar, 128 F.3d 830-31. immunity ruling. Special interrogatories related to the qualified immunity defense are not improper per se, but they must be carefully crafted so that the fact-finder’s role is limited to determining whether the underlying facts are as the plaintiff has alleged or proved.”) (internal citations and quotation marks omitted) with Turner v. Arkansas Ins. Dept., 297 F.3d 751, 754 (8th Cir. 2002) (in discussing an official’s burden to come forward with “undisputed and material facts that demonstrate that his actions were reasonable under the circumstances[,]” the Court stated that “[i]f such facts are undisputed, then that is a question of law to be reviewed by a court; if not, then it is a question for a jury and summary judgment is improper.”) 22 Later, in Curley I, we cited Sharrar for the proposition “that a jury can evaluate objective reasonableness when relevant factual issues are in dispute.”11 298 F.3d at 279. We also went on to say, however, that it would not be inappropriate “for a judge to decide the objective reasonableness issue once all the historical facts are no longer in dispute[,]” and we suggested the use of special interrogatories as a means to that end. Id. Finally, in a line of cases beginning with Doe v. Groody, we began highlighting that “qualified immunity is an objective question to be decided by the court as a matter of law.” Carswell, 381 F.3d at 242 (citing Doe, 361 F.3d at 238). In Carswell, we elaborated on that point. We explained that the jury “determines disputed historical facts material to the qualified immunity question[,]” and we again suggested that “District Courts may use special interrogatories to allow juries to perform this function,” id. (citing Curley I, 298 F.3d at 279). We emphasized that “[t]he court must make the ultimate determination on the availability of qualified immunity as a matter of law.” Id. That emphasis reemerged in Harvey, when we cited Carswell and Doe for the 11 We are not suggesting that the objective reasonableness of an officer’s view of the law may be submitted to the jury. Rather, we are recognizing that, when material issues of fact are in dispute, our past precedents, in particular Karnes, Sharrar, and Curley I, have allowed the jury to resolve those disputes and also to determine the objective reasonableness of the officer’s conduct in light of the facts. 23 proposition that qualified immunity is purely a question of law to be answered by the court. 421 F.3d at 194 n.12. It appears that much of the discussion in Carswell was dicta, since we were actually affirming in that case the grant of judgment for the defendant as a matter of law, following the presentation of the plaintiff’s case at trial. 381 F.3d at 239, 245. In a technical sense, then, the dicta is not binding. See Abdelfattah v. United States Dept. of Homeland Security, 488 F.3d 178, 185 (3d Cir. 2007) (“While ‘[i]t is the tradition of this court that the holding of a panel in a precedential opinion is binding on subsequent panels,’ Internal Operating Procedure 9.1, it is also well established that we are not bound by dictum in an earlier opinion.”) (citing Mariana v. Fisher, 338 F.3d 189, 201 (3d Cir. 2003)). It has nevertheless been repeated and understood as a definitive direction on the respective roles of judge and jury when a qualified immunity defense is raised. See, e.g., Johnson v. Anhorn, 416 F. Supp. 2d 338, 361 (E.D. Pa. 2006) (“[Q]ualified immunity is an objective question to be decided by the court as a matter of law... . The jury, however, determines disputed historical facts material to the qualified immunity question.”) (quoting Carswell, 381 F.3d at 242); Iwanejko v. Cohen & Grigsby, P.C., 2006 WL 2659109, at 9 (W.D. Pa. Sept. 15, 2006) (quoting Carswell and stating, “in the Third Circuit ‘qualified immunity is an objective question to be decided by the Court as a matter of law.’”); Brown v. City of Camden, 2006 WL 2177320, at 7 (D.N.J. July 27, 2006) (citing Carswell and saying “In this Circuit, the Court must make the ultimate determination on the availability of qualified immunity as a matter of law.”). 24 There is some irony in this, since Carswell relied on Curley I and Sharrar, correctly citing them as support for the proposition that objective reasonableness is a question of law. But neither Curley I nor Sharrar stand for the related proposition that the question of objective reasonableness cannot be presented to a jury. Indeed they both teach “that a jury can evaluate objective reasonableness when relevant factual issues are in dispute.” Curley I, 298 F.3d at 279; see also Sharrar, 128 F.3d at 830-31. Nevertheless, the Carswell approach, despite its limitations, see infra at section III. C., appears to have taken root and to represent the pattern and practice both in our Circuit and much of the rest of the country. We therefore take the opportunity to reiterate and clarify a central message from that case: whether an officer made a reasonable mistake of law and is thus entitled to qualified immunity is a question of law that is properly answered by the court, not a jury. Carswell, 381 F.3d at 242. When a district court submits that question of law to a jury, it commits reversible error. Question Three on the liability verdict sheet was evidently intended to reach the question of qualified immunity.12 However, as we discuss further below, the 12 We acknowledge again that our language in Curley I left open the possibility of giving that question to the jury. Discussing “the procedure for deciding the immunity question when the existence of disputed issues of fact precludes disposition on summary judgment,” 298 F.3d at 278, we stated: 25 We addressed the issue in Sharrar, in which we observed that the “reasonableness of the officers' beliefs or actions is not a jury question,” 128 F.3d at 828, but qualified that observation by later noting that a jury can evaluate objective reasonableness when relevant factual issues are in dispute, id. at 830-31. This is not to say, however, that it would be inappropriate for a judge to decide the objective reasonableness issue once all the historical facts are no longer in dispute. A judge may use special jury interrogatories, for instance, to permit the jury to resolve the disputed facts upon which the court can then determine, as a matter of law, the ultimate question of qualified immunity. Id. at 279. We cannot fault the District Court for following our instructions on remand. Unlike our dissenting colleague, we do not view Curley I as making “clear the respective roles of the judge and jury in cases such as this,” post at 18. To the extent Curley I can be read as allowing the District Court to submit the question of qualified immunity to the jury we are hard pressed to say the District Court erred in doing so. We hope, however, that it will now be clear that the second step in the Saucier analysis, i.e., whether an officer made a reasonable mistake about the legal constraints on police action and is entitled to qualified immunity, is a question of law that is exclusively for the court. When the ultimate question of the objective reasonableness of an officer’s behavior involves 26 question as framed actually pertains to whether there was any constitutional violation at all. Since it properly presented an essentially factual question regarding the constitutional violation, it was not error for the jury to consider it. C. The Challenge of Preserving “Totality of Circumstances” Review As this case demonstrates, trying to separate the ultimate from the underlying questions is no easy matter and can have a disturbing, unintended consequence. It can undermine the basic principle that both the threshold constitutional question and the immunity question are to be decided on the totality of the circumstances. Fundamental fairness dictates a totality-of-the- circumstances review, since the test for reasonableness “is not capable of precise definition or mechanical application,” Bell v. Wolfish, 441 U.S. 520, 559 (1979). It depends on all of the chaotic details that emerge in real time in real life.13 Yet the tightly intertwined issues of fact and law, it may be permissible to utilize a jury in an advisory capacity, see infra at sec. III.C., but responsibility for answering that ultimate question remains with the court. 13 We have here a fundamental parting of the ways with the dissent. While our colleague sees this case as coming down to, to use her analogy, one domino in the sequence of events, post at 12, we feel compelled to recognize that reality is a 27 method that we and many other courts have taken to address the mixed legal and factual questions posed by the Saucier test cannot easily, perhaps cannot ever, capture those circumstances in their totality. When one picks and chooses a few questions to pose to a jury to ferret out historical facts, staying away from asking the broader question of what constitutes reasonable behavior under those facts, one cannot help but focus attention on some events to the diminution or exclusion of others. In short, a totality-of-the-circumstances test is replaced by a test focusing on those few circumstances featured in the questions a court is able and willing to articulate. The District Court clearly saw that problem in this case. As quoted before, the judge observed that the analysis in this case could not properly be shrunk into the few moments immediately before Klem shot Curley, but instead must be decided in light of all the events which had taken place over the course of the entire evening. Post-trial Opinion, 2006 WL 414093, at 2. The desire to avoid the kind of difficulty presented here is perhaps what has motivated other courts to sanction the alternative approach of permitting the question of objective reasonableness to go to juries. See Sloman, 21 F.3d at 1468 (“[S]ending the factual issues to the jury but reserving to the judge the ultimate ‘reasonable officer’ determination leads to serious logistical difficulties. Special jury verdicts would unnecessarily good deal more complicated than the simple causality evident in falling dominoes. 28 complicate easy cases, and might be unworkable in complicated ones.”). In spite of the foregoing problem inherent in articulating specific questions to address factual issues, our most current precedent counsels that course.14 However, while the judge must make the ultimate determination regarding the objective reasonableness of challenged behavior, that does not mean that the use of an advisory jury is foreclosed. We need not consider the propriety of such a step under the circumstances presented here, though, because the jury in this case was not acting in an advisory capacity. The Court put to the jury the question of the objective reasonableness of Klem’s actions, and the Court upheld the verdict rendered. 14 We note that in the Supreme Court’s recent decision in Scott, 127 S. Ct. 1769 (2007), the Court stated that, because the case “was decided on summary judgment, there [had] not yet been factual findings by a judge or jury ... .” Id. at 1774 (emphasis added). Without wanting to read too much into that statement, since it may refer to nothing more than a case in which the parties waive any right to a jury, it appears the Court at least contemplated a circumstance where a judge may resolve factual issues. Certainly the dissent in Scott was concerned about judicial fact finding. See id. at 1781 (Stevens, J., dissenting) (“Relying on a de novo review of a videotape ..., eight of the jurors on this Court reach a verdict that differs from the views of the judges on both the District Court and the Court of Appeals who are surely more familiar with the hazards of driving on Georgia roads than we are.”). 29 IV. A. The Jury Was Not Choosing Between Alternative Theories of Liability The jury was not facing a choice of alternative liability theories driven by “outcome-determinative facts,” as Curley would have it. See Post-trial Opinion, 2006 WL 414093, at 4. The District Court rightly rejected that view. We did not, in Curley I, presume to set forth any theories of liablilty, let alone the strict alternatives Curley characterizes our opinion as requiring. We simply identified “disputed issues of material fact with regard to at least two key events – the inspection of the suspect’s vehicle and the actual confrontation between Klem and Curley.” 298 F.3d at 281. As Curley sees it, resolution of the factual issues in his favor was not merely a necessary condition for him to prevail, it was an entirely sufficient condition. But that was never so. Our pointing to “at least two key events[,]” id. (emphasis added), accurately implied that there were more facts on the table than the two areas of dispute we singled out for discussion. Consistent with our own cases and with precedent from the Supreme Court, we could not have directed the District Court to ignore the totality of the circumstances and to focus instead on those two areas. Even if those specifically identified factual areas were the only ones to be considered, it is an unwarranted leap to say that the jury’s responses to selected yes-or-no questions means that only one set of inferences and conclusions can be 30 drawn from those responses. For example, the jury’s answer of “no” to the question of whether “Officer Curley raise[d] his gun to point directly at Trooper Ron Klem several times during ‘the confrontation’” might mean that the jury decided that Curley had raised his gun to point at Klem only once or twice, rather than “several times,” as the question asks.15 One need not draw the inference that Curley demands. Indeed, we cannot. Though multiple inferences are possible, we must draw all inferences in Klem’s favor, rather than Curley’s, since we are reviewing a verdict for Klem. See McGreevy v. Stroup, 413 F.3d 359, 364 (3d. Cir. 2005) (on a motion for judgment as a matter of law under Federal Rule 50(a), evidence must be viewed “in the light most favorable to the nonmoving party”). In short, any ambiguity in the interrogatories and the answers to them must, at this stage, be interpreted against Curley. The District Court therefore did not err in rejecting Curley’s “alternative theories of liability” view of the verdict sheet. B. The Focus Should Have Been on the Threshold Question Where the District Court did go astray was in assuming that a constitutional violation had occurred and then applying its efforts to answering the question of immunity. The Court’s confusion appears to have been the product both of 15 Given that Curley acknowledged pointing the gun in the direction of the Camry and that Klem was standing next to the car, it is not fanciful to believe that the jury could have interpreted the question as described. 31 language in our Curley I opinion and of the intertwined questions of objective reasonableness posed by the two prongs of the Saucier test when applied to this case. The panel in Curley I addressed the question of whether Klem’s conduct violated Curley’s constitutional rights in the summary judgment context, and thus “consider[ed] only the facts alleged by Curley, taken in the light most favorable to him.” Curley I, 298 F.3d at 280. In determining that, under Curley’s version of the facts, he had established a violation of his constitutional rights, we said: [T]hese facts, viewed in the light most favorable to Curley, are sufficient to support the claim that Klem’s shooting of Curley constituted an unreasonable seizure, violative of Curley’s rights under the Fourth Amendment. ... [W]e find that under Curley’s account of events, it was unreasonable for Klem to fire at Curley based on his unfounded, mistaken conclusion that Curley was the suspect in question. Id. at 280 (emphasis added). The District Court apparently read our opinion as establishing that Curley’s constitutional rights were violated. In its ruling on post-trial motions, the District Court stated that “there was a constitutional violation in that Officer Curley had a right not to be shot by Trooper Klem.” 2006 WL 414093, at 1. That, however, is an oversimplification and a misreading of Curley I. Whether Klem committed a constitutional tort turns not on the simple fact that he shot the wrong man. That would end the inquiry 32 before it began. The question is whether Klem’s use of force, even though mistakenly directed, was objectively reasonable in light of the totality of the circumstances. That question had yet to be answered when Curley I was decided, since a trial was required. There is no substitute for “slosh[ing one’s] way through the factbound morass of ‘reasonableness.’” Scott, 127 S. Ct. at 1778. Thus, our earlier opinion was not a decision on whether, under all of the facts and circumstances of the case, Klem’s conduct violated Curley’s constitutional rights. The jury was not bound at trial, and the District Court was not bound post-trial, by our earlier statements involving a hypothetical set of facts favoring Curley, since the facts and inferences actually found by the jury were clearly different than those which we were required to posit in Curley I when considering the summary judgment order.16 16 The procedural posture of Curley I provides another key reason why we cannot agree with the dissent. Our colleague takes as a given that Curley I established alternative theories of liability based on a “simple syllogism,” post at 13-14, but Curley I was in a procedural posture that required every inference to be drawn for Curley. It thus did not present an opportunity to frame a set of factual questions to constrain the jury’s fresh look at the evidence. The jury was not constrained by the Curley I opinion’s necessarily biased view of the facts, and the jury was therefore free to consider the entire set of facts facing Klem when determining whether Klem’s conduct violated Curley’s constitutional rights. 33 Confusion between the threshold constitutional inquiry and the immunity inquiry is also understandable given the difficulty courts have had in elucidating the difference between those two analytical steps.17 At the risk of understating the challenges inherent in a qualified immunity analysis, we think the most helpful approach is to consider the constitutional question as being whether the officer made a reasonable mistake of fact, while the qualified immunity question is whether the officer was reasonably mistaken about the state of the law. With that in mind, we turn to the questions presented to the jury in this case. The constitutional liability question posed to the jury, Question Two on the verdict sheet, was “Did Trooper Ron Klem act in an objectively reasonable manner in shooting Officer Curley during the confrontation?” Question Three, designed as the immunity question, was posed as, “Was Trooper Ron Klem’s mistake in firing his weapon objectively reasonable?” The difference between those two questions is essentially semantic, the only difference being that Question Three makes explicit what was 17 The Saucier opinion itself was generated by the confusion inherent in such conceptually close questions. See Saucier, 533 U.S. at 197 (“The matter we address is whether the requisite analysis to determine qualified immunity is so intertwined with the question whether the officer used excessive force in making the arrest that qualified immunity and constitutional violation issues should be treated as one question, to be decided by the trier of fact.”). 34 already obvious and conceded in the case: that the shooting was a mistake. For practical purposes, then, the analysis of objective reasonableness that the District Court undertook under the rubric of an immunity question actually applies better to the preliminary constitutional question. The immunity step of the Saucier test is typically focused on established legal standards and requires a review of relevant case law, a review a jury simply cannot undertake. See Saucier, 533 U.S. at 205 (“The concern of the immunity inquiry is to acknowledge that reasonable mistakes can be made as to the legal constraints on particular police conduct.”). However, the constitutional analysis focuses on the factual circumstances of the incident and asks whether the officer made a reasonable mistake of fact. Question Three did exactly that. It asked not whether Trooper Klem made a mistake of law – wrongly believing that it was legal to shoot the wrong person – but whether it was reasonable for him to make the factual mistake of believing Officer Curley was the armed and dangerous Bailey. Therefore, if the jury properly determined that Klem made an objectively reasonable mistake when he shot Curley, then it found that there was no constitutional violation, and the District Court did not err in entering a verdict in favor of 35 Trooper Klem.18 We turn now to that question of the sufficiency of the evidence. C. The Jury’s Verdict is Supported by the Evidence The jury’s verdict on the objective reasonableness of Trooper Klem’s actions is well supported by the record. There are many facts that the jury was entitled to rely on that were not in dispute, including Bailey’s behavior prior to and during the high speed car chase that led to the George Washington Bridge. Bailey had shot and killed a police officer, had shot at another officer, had stolen a police car, had then carjacked the Camry from a rest stop on the New Jersey Turnpike, had launched a high speed chase on the Turnpike and, during that chase, had fired shots at Klem and other officers, wounding an officer and hitting Klem’s windshield. Furthermore, whether or not Klem knew exactly what had occurred, no one disputes that he came on the scene in the immediate aftermath of Bailey’s creating additional havoc by crashing into the Pathfinder. In short, no one 18 The fact that the District Court relied on Question Three as answering the qualified immunity question and entered a verdict based on Trooper Klem deserving qualified immunity is not reversible error. Because Trooper Klem was entitled to a verdict in his favor either if there was no constitutional violation or if he was entitled to qualified immunity, the error in the District Court’s analysis was harmless. Hill v. Laisz, 435 F.3d 404, 411 (3d Cir. 2006) (holding that error is harmless where it is “highly probable” that the error did not affect the outcome of the case). 36 disputes that Bailey was actively evading arrest after committing several severe crimes, that he posed a serious danger to both the police and public, and that Klem could properly approach the scene prepared to use deadly force. In fact, Curley himself did so. He testified that, when he began to approach the Camry, his gun was drawn. The very real danger that both Curley and Klem perceived at the toll plaza was intensified by the presence of numerous innocent bystanders. Curley’s solicitude for the safety of the driver of the Pathfinder is not just commendable; it reflects the well-founded fear that people who got out of their cars were in danger of being shot. Added to all of this is the jury’s finding that, when Klem approached the wrecked Camry, he saw a toll booth attendant signaling him to look to the middle of the toll plaza. That is where Curley was standing with a gun in his hands. In Curley’s view, none of those facts is of any moment, since Klem’s failure to look into the Camry is dispositive. According to Curley, had Klem looked, he would have seen Bailey’s dead body and there would have been no confrontation.19 However, as we have stated several times, 19 This, of course, is the dissent’s view as well, post at 11- 12, and we do not suggest that this is illogical, only that it is not the exclusively logical view. We stated in Curley I that Klem knew there was only one suspect and, “had Klem known of Bailey’s suicide, it would have been clearly unreasonable for him later to confuse Curley with the suspect.” 298 F.3d at 281. Hence, the question of whether 37 the reasonableness of Klem’s conduct must be examined based on the totality of the circumstances, and the inquiry cannot be collapsed into a single instant, particularly not when, at that instant, Klem’s vision was being drawn by the toll booth attendant toward Curley, standing in the plaza with a gun.20 Thus, when we examine all of the facts and circumstances, the jury’s verdict that Klem acted reasonably is supported by the evidence. Klem looked in the Camry is highly relevant. But it is not outcome determinative. We did not equate looking in the Camry with knowledge of Bailey’s death, since it was conceivable that a factfinder could have decided that an objectively reasonable officer could look in the Camry and still not see Bailey, no matter how obvious the body might have been to others not in that officer’s unique position. It was also conceivable that a factfinder could conclude, as the jury apparently did, that despite Klem’s overlooking information that could have enlightened him about the suicide, his actions in totality and under the pressure of the moment were such that his failure to look in the car did not make the shooting objectively unreasonable. 20 The jury’s conclusion that Klem’s failure to look into the Camry was unreasonable is not beyond dispute. Given all else that had occurred and was occurring, it can be argued that looking at the gesticulating toll booth attendant, rather than into the car, may not have been the most reasonable action but was still within the bounds of reason. However, since we are upholding the verdict on other grounds, we do not address that issue. 38 The mistake Klem made has undoubtedly been terrible in its long-term consequences for Officer Curley and his family, and we do not for a moment discount the pain, sorrow, expense, and frustration that it has visited on them in their innocence. But a mistake, though it may be terrible in its effects, is not always the equivalent of a constitutional violation. In Curley I, we acknowledged “the great pressure and intensity inherent in a police officer’s hot pursuit of a suspect known to be armed and highly dangerous ... .” 298 F.3d at 280. That would amount to little more than lip service, were we to reverse the jury’s verdict and the District Court’s thoughtful decision on the post-trial motions. “[P]olice officers are often forced to make split-second judgments – in circumstances that are tense, uncertain, and rapidly evolving – about the amount of force that is necessary in a particular situation.” Graham, 490 U.S. at 397. Those were the circumstances facing both Trooper Klem and Officer Curley at the George Washington Bridge toll plaza. Viewed from that perspective, Saucier, 533 U.S. at 205, the seizure effected by the mistaken shooting was not unreasonable under the Fourth Amendment. It therefore was not a constitutional violation. V. For the foregoing reasons, we will affirm the judgment of the District Court on the ground that no constitutional violation occurred. CURLEY v. KLEM (“Curley II”) 39 No. 05-4701 ROTH, Circuit Judge, dissenting: The jury’s findings make clear that, were it not for Trooper Klem’s unreasonable actions, the tragic shooting of Officer Curley would never have occurred. In the special interrogatories, the jury found that the sole perpetrator was dead and visibly sprawled across the passenger seat of the Camry at the time Klem approached it, and that Klem came within an arm’s length of the Camry’s passenger side window, yet failed to look into the car to check for the perpetrator’s body. Klem admitted at trial that, had he looked into the Camry and seen the perpetrator lying there, Klem would not have confronted and shot Curley. Klem would have holstered or lowered his gun, thus breaking the chain reaction of events leading to the shooting, and Curley would have walked away unharmed. In Question 1 of the liability verdict sheet, the jury had to decide whether Klem’s failure to break the chain reaction – by failing to look into the Camry – was an objectively reasonable mistake of fact, in light of the totality of the circumstances. The jury concluded that it was not. Based on these facts, I cannot agree with the majority’s conclusion that the jury returned a verdict for Klem. The exact opposite is true. The jury answered Question 1 in favor of Curley, which established a constitutional violation. Although the jury answered Question 3 in favor of Klem, this question should never have been posed, as it asked the ultimate question 40 of qualified immunity and encompassed purely legal issues reserved exclusively for the court. The majority concedes that such a question is outside the province of the jury, and our prior precedents, including our prior decision in this case, have never stated otherwise. Therefore, in order to justify its decision to affirm, the majority takes a revisionist view of history and refashions Question 3 into a factual, rather than legal, question. The majority does so notwithstanding the fact that the language and structure of the verdict sheet and the understanding of the District Court and the parties clearly demonstrate that Question 3 was an improper legal question. For these reasons and those that follow, I respectfully dissent. Question 3 should be stricken, the judgment for Klem should be vacated, and this case should be remanded in order to permit the District Court, rather than the jury, to resolve the ultimate question of qualified immunity. If the District Court were to conclude that immunity is not warranted under clearly established law, judgment should be entered in favor of Curley and the case should proceed to a damages determination. I. BACKGROUND In Curley v. Klem, 298 F.3d 271 (3d Cir. 2002) (“Curley I”), we reversed the summary judgment for Klem on Curley’s excessive force claim because the District Court failed to “recognize the existence of disputed historical facts that are clearly material to the question of objective reasonableness.” Id. at 281. Specifically, we identified a series of disputed facts relating to “two key events – the inspection of the suspect’s vehicle and the actual confrontation between Klem and Curley.” 41 Id. We discussed each event in detail, under separate topic headings entitled “The Body in the Camry” and “The Confrontation,” id. at 281-282, and noted their sequential relationship to one another: When Klem arrived at the toll plaza, he was unaware that his suspect had just shot and killed himself while sitting inside the stolen Camry. But it is uncontroverted that Klem knew there was only one perpetrator. Thus, had Klem known of Bailey’s suicide, it would have been clearly unreasonable for him later to confuse Curley with the suspect. Assuming that a reasonable officer in Klem’s position would have looked inside the Camry upon arriving at the scene, a key issue becomes whether Klem did, in fact, look inside the Camry’s window. Id. at 281 (emphasis added). We noted that, while qualified immunity is supposed to act as immunity from suit, not just liability, “the reality [is] that factual disputes often need to be resolved before determining whether the defendant’s conduct violated a clearly established constitutional right.” Id. at 278. We noted that “[a] judge may use special jury interrogatories, for instance, to permit the jury to resolve the disputed facts upon which the court can then determine, as a matter of law, the ultimate question of qualified immunity.” Id. at 279. Our analysis was colored by the Supreme Court’s directive, in Saucier v. Katz, 533 U.S. 194 (2001), that Fourth Amendment qualified immunity analysis “must be undertaken in light of the specific context of the case, not as a broad general proposition.” Id. at 201 (emphasis added). 42 In accordance with our directives in Curley I, the District Court submitted a series of special interrogatories to the jury at the conclusion of trial. These 10 interrogatories were derived from the material fact disputes we had identified in our decision in Curley I. Five interrogatories sought to resolve fact disputes relating to the extent of Klem’s inspection of the Camry. All of these interrogatories were answered in favor of Curley in that they tended to demonstrate that Klem had acted unreasonably by failing to look into the Camry, where he would have seen the perpetrator’s dead body.21 The other five interrogatories addressed Klem’s subsequent confrontation with Curley – 21 These interrogatories are as follows. Interrogatory 1 asked: “At the time Trooper Klem approached the Camry, was the perpetrator’s body on the front seat of the car?” The jury answered: “Yes.” Interrogatory 2 asked: “At the time Trooper Klem approached the Camry, was the perpetrator’s body on the passenger side floor of the car?” The jury answered: “No.” Interrogatory 3 asked: “When Trooper Ron Klem was within about an arm’s length from the passenger side window of the Camry, did he look into the window of the Camry to see if the perpetrator was in the car?” The jury answered: “No.” Interrogatory 4 asked: “Regardless of where the perpetrator’s body was located in the Camry, should it have been visible to someone looking in the passenger side window from where Trooper Klem was positioned?” The jury answered: “Yes.” Interrogatory 5 asked: “Did Trooper Ron Klem make an objectively reasonable effort to observe into the Camry to determine if the perpetrator was inside the Camry?” The jury answered: “No.” 43 which, by Klem’s own admission, never would have happened had Klem acted reasonably by looking into the Camry. Two of these interrogatories were answered in favor of Curley (in that they tended to demonstrate that Klem confronted Curley in an unreasonable manner),22 one interrogatory was answered in favor of Klem (in that it tended to demonstrate that Klem had acted reasonably),23 and two interrogatories were left unanswered due to the jury’s failure to reach a unanimous decision on them.24 22 These interrogatories are as follows. Interrogatory 7 asked: “Did Officer Curley raise his gun to point directly at Trooper Ron Klem several times during “the confrontation?” The jury answered: “No.” Interrogatory 8 asked: “At the time Officer Curley was shot, was Officer Curley’s gun coming up to aim at Trooper Ron Klem?” The jury answered: “No.” 23 This interrogatory, Interrogatory 6, asked: “Was it objectively reasonable for Trooper Ron Klem to believe that toll collector Jenkins signaled to him with an arm motion towards the east side center of the plaza?” The jury answered: “Yes.” 24 These interrogatories are as follows. Interrogatory 9 asked: “Was Officer Curley’s uniform visible as a police uniform from the position where Trooper Ron Klem was standing?” Interrogatory 10 asked: “Was it objectively reasonable for Trooper Ron Klem to believe that the individual he observed holding a weapon was wearing civilian clothing?” 44 The District Court also submitted to the jury a separate “Liability Verdict Sheet” premised on and guided by our discussion in Curley I. Although the majority opinion reproduces the four liability questions in full, the majority fails to include the instructions that accompanied these questions. Because these instructions are critical to understanding the meaning of the questions themselves, I set forth the verdict sheet in its entirety, as returned by the jury, below: LIABILITY VERDICT SHEET After you have finished answering the written interrogatories, please proceed to liability, and, if appropriate, damage questions. 1. Did Trooper Ron Klem’s failure to act in an objectively reasonable manner in observing the Camry prevent him from seeing the perpetrator’s body in the Camry? X Yes No 2. Did Trooper Ron Klem act in an objectively reasonable manner in shooting Officer Curley during the confrontation? X Yes No If you answered Yes to Question 1 and/or No to Question 2, proceed to Question 3. 45 If you answered No to Question 1 and also Yes to Question 2, then go no further. Stop deliberating and inform the attendant that you have reached the verdict. If not, proceed to Question 3. 3. Was Trooper Ron Klem’s mistake in firing his weapon objectively reasonable? X Yes No If you answered No to Question 3, then proceed to Question 4. If you answered Yes to Question 3 then proceed no further. Stop deliberating and inform the attendant that you have reached a verdict. 4. Did the plaintiff suffer damages that were proximately caused by Trooper Ron Klem’s conduct? Yes No If you answered Yes to Question 4 you must proceed to the Damages Verdict Sheet. If you answered No to Question 4, proceed no further. Stop deliberating and inform the attendant that you have reached a verdict. 46 There is certainly some ambiguity in the verdict sheet. However, as I will discuss below, I believe it is clear that – in light of the special interrogatories, the verdict sheet instructions, and other record evidence – Questions 1 and 2 represented alternate theories of liability, and Question 3 represented the ultimate qualified immunity question. Although Questions 1 and 2 were more or less in accordance with our directives in Curley I, Question 3 was not – and it never should have been included on the verdict sheet. Upon receiving the jury’s answer to Question 3, the District Court promptly entered judgment for Klem on that basis, without any further analysis, in a two-page judgment order. See 9/29/05 Order. In its post-trial opinion, the District Court made clear that the issue of qualified immunity was out of its hands and had been delegated to the jury in Question 3: “Question 3 properly asks the jurors to make the finding that is inherent in the remand, and in answering it as they did, unanimously, this jury decided the issue of qualified immunity in Trooper Klem’s favor.” Curley v. Klem, No. 98-5256, 2006 WL 414093, at 5 (D.N.J. Feb. 21, 2006) (emphasis added). By entering judgment for Klem on the basis of Question 3, the District Court disregarded the jury’s answers to the special interrogatories, overrode the jury’s finding of liability in Question 1, and improperly delegated the ultimate question of qualified immunity to the jury. II. DISCUSSION First, I will explain why Questions 1 and 2 were alternate theories of liability. Second, I will explain why Question 3 47 asked the ultimate question of qualified immunity, and thus should be stricken. Third, I will explain how the District Court should have handled the issue of qualified immunity. A. Questions 1 & 2 It is self-evident that Klem shot the wrong man. That mistake alone, however, does not establish a Fourth Amendment violation for unreasonable seizure. Rather, what must be shown is that the facts of the case rendered it objectively unreasonable for Klem to mistake Curley for the fleeing perpetrator and then use deadly force to seize him. As we noted in Curley I, there are at least two ways in which the jury could have found the mistaken identification and corresponding shooting to be objectively unreasonable. First, the jury could have concluded that Klem acted unreasonably by failing to check the Camry for the perpetrator’s body, which directly led to the mistaken identification and shooting. Indeed, we explicitly stated in Curley I that, “had Klem known of Bailey’s suicide, it would have been clearly unreasonable for him later to confuse Curley with the suspect.” 298 F.3d at 281. Second, even if Klem had acted reasonably in failing to check the Camry, the jury could still find that Klem acted unreasonably in mistaking Curley for the perpetrator during the subsequent confrontation depending on the circumstances of that event. Id. at 282. Although these two theories were not the only potential avenues for liability, they were the focus of our opinion in Curley I and influenced the District Court’s decision to place Questions 1 and 2 on the verdict sheet as alternative theories of liability. The trial record reflects that the parties and the District 48 Court understood and intended Questions 1 and 2 to be alternate liability questions. This understanding was in line with the verdict sheet instructions directing the jury to proceed to Question 3 “[i]f you answered Yes to Question 1 and/or No to Question 2” (emphasis added). The fact that an answer for Curley on either Question 1 or 2 warranted consideration of Question 3 suggests that Questions 1 and 2 were in fact alternate and independent liability questions. They had to be, because an answer for Curley on either question took the jury to the same place. Questions 1 and 2 operated independently and a finding for Curley on either one was sufficient to establish a constitutional violation. Klem argues that Question 1 was actually a special interrogatory, as opposed to an independent liability question. This argument makes little sense in light of the fact that all other special interrogatories were placed on a separate sheet entitled “Special Interrogatories” and Question 1 appeared on the “Liability Verdict Sheet.” Klem also argues that the District Court would have included instructions to skip Question 2 upon a finding in favor of Curley on Question 1 if those two questions were actually alternate and independent theories of liability. This argument seems plausible at first blush, but Curley rightly points out that it was sensible for the District Court to instruct the jury to answer both questions, despite being independent of one another, in case this Court were to invalidate one of the two theories of liability on appellate review – a reasonable concern given the complexity and history of this case. Finally, Klem argues that our comment in Curley I that “a key issue” – as opposed to the key issue – was “whether Klem did, in fact, look inside the Camry’s window,” id. at 281, shows that it is 49 impossible for Question 1 to be outcome-determinative. This argument falls short because it fails to appreciate the fact that identifying a proximate cause of an injury can be outcome- determinative even if it is not the only proximate cause of that injury. With regard to this last argument, the majority adopts a somewhat similar view by arguing that one event – the unreasonable failure to inspect the Camry – cannot alone support liability because the totality of the circumstances must be considered. I do not dispute that the totality of the circumstances must be considered and I fully agree that “[a]ll of the events leading up to the pursuit of the suspect are relevant.” Carswell v. Borough of Homestead, 381 F.3d 235, 243 (3d Cir. 1999) (citing Abraham v. Raso, 183 F.3d 279, 292 (3d Cir. 1999)). Indeed, the jury was instructed to consider the totality of the circumstances,25 and did so in answering Question 1. Application of the totality of the circumstances standard, however, does not make it impossible for one particular circumstance to be outcome-determinative, as it was here, because it is entirely possible that some circumstances are more important that others. See Abraham, 183 F.3d at 292 (disagreeing with the proposition that “all preceding events are equally important” in a similar Fourth Amendment case). We highlighted this fact in Curley I when we explained that Klem’s 25 In its charge to the jury, the District Court stated that “[a]ll of the events leading up to the pursuit of the suspect are relevant,” apparently quoting Carswell verbatim. App. at T1166. 50 unreasonable failure to look into the Camry would be important enough to render his misidentification and shooting of Curley immediately thereafter unreasonable; in other words, the first unreasonable act would necessarily carryover and render the second act unreasonable as well. See Curley I, 298 F.3d at 281. This is so because the high-speed chase was composed of a sequence of events forming a chain reaction, like a row of falling dominoes. One event caused the next event which caused the next. Had Klem looked into the Camry for the sole perpetrator – which is what the jury concluded an objectively reasonable police officer would have done in light of the circumstances26 – a key domino would have been removed and the chase would have come to an end. Indeed, Klem admitted at trial that, had he seen the perpetrator in the Camry, he never would have shot Curley. App. at T1016. Klem’s admission negates any suggestion that, even if he knew of the perpetrator’s death, Curley’s subsequent approach with a gun might have 26 In Curley I, we “[a]ssum[ed] that a reasonable officer in Klem’s position would have looked inside the Camry upon arriving at the scene.” 298 F.3d at 281. Our assumption was borne out by the jury’s findings in Interrogatory 5 and Question 1. In Interrogatory 5, the jury was asked, “Did Trooper Ron Klem make an objectively reasonable effort to observe into the Camry to determine if the perpetrator was inside the Camry?,” and answered, “No.” In Question 1, the jury was asked, “Did Trooper Ron Klem’s failure to act in an objectively reasonable manner in observing the Camry prevent him from seeing the perpetrator’s body in the Camry?,” and answered, “Yes.” 51 nevertheless presented a new danger that would have warranted the use of deadly force. The District Court correctly instructed the jury: “The question is whether, in the circumstances here, a reasonable officer would not have made the mistake that Trooper Klem made.” App. at T1166-67. By concluding, in Question 1, that a reasonable officer would have looked in the Camry – where, according to the jury’s findings in the special interrogatories, Bailey was lying in plain view – the jury answered the dispositive question of liability in favor of Curley. For Klem’s shooting of Curley to have been reasonable, Klem’s misidentification of Curley must have been reasonable as well. The jury concluded that Klem’s misidentification was not reasonable. Therefore, the shooting could not have been reasonable.27 It is this simple syllogism, premised upon the law 27 This is so notwithstanding the jury’s answer to Question 2, which, as discussed above, was answered in case this Court were to invalidate Question 1. The shooting during the confrontation was unreasonable by necessity – due to the sequential nature of the events – once the jury concluded that it was unreasonable for Klem not to look into the car. The unreasonableness of Klem’s failure to look into the Camry carried over and rendered Klem’s misidentification during the confrontation unreasonable as well. This “carry over” effect can be understood with a hypothetical. If, during a high- speed car chase, an officer unreasonably turned off his police radio and therefore did not hear that the perpetrator being pursued had been stopped, by necessity it would be unreasonable if the officer then rammed an innocent driver, 52 of the case as set forth in Curley I, see In re City of Phila. Litig., 158 F.3d 711, 722 (3d Cir. 1998) (applying law of the case doctrine in a similar Fourth Amendment case), that the majority fails to appreciate. For these reasons, I would conclude that, by answering Question 1 in favor of Curley, the jury found that Klem had committed a constitutional violation. In this case, proof of an unreasonable action that directly causes a later action that might otherwise be reasonable but nevertheless should not have occurred should be enough to prove a violation.28 Having concluded that the jury found a constitutional violation, I wrongly identified as the feeling perpetrator, after the unreasonable action of turning off the radio – an unreasonable action directly responsible for the misidentification and ramming of the innocent driver. Similarly, Klem’s misidentification of Curley is unreasonable due to the unreasonable action that directly preceded it – the failure to look into the Camry – which directly caused the misidentification and shooting to occur. 28 This is not to say that in all circumstances one unreasonable action that occurs within a series of reasonable actions necessarily establishes a violation. For example, if the hypothetical officer discussed above, supra note 7, turned his radio back on before any relevant information was transmitted, the officer’s misidentification later would not necessarily constitute a violation simply because of the officer’s earlier unreasonable action of turning off his radio. 53 consider whether we should permit that finding to be negated by Question 3. B. Question 3 As I noted above, there is no dispute that Klem shot the wrong man. Therefore, Questions 1 and 2 did not ask whether Klem had made a mistake, since that was conceded; rather, they asked whether Klem’s mistake was an objectively reasonable one, for Fourth Amendment purposes, in light of the factual circumstances at hand. That is, Questions 1 and 2 resolved step one of the Saucier test concerning whether a constitutional violation had occurred. Since the jurors found a constitutional violation by answering “Yes” to Question 1, they next considered Question 3, which asked, “Was Trooper Ron Klem’s mistake in firing his weapon objectively reasonable?” The majority acknowledges that “Question Three on the liability verdict sheet was evidently intended to reach the question of qualified immunity,” i.e., Saucier step two, but nevertheless concludes that Question 3 “actually pertains to whether there was any constitutional violation at all.” Maj. Slip Op. at 27. The majority’s conclusion is unfounded because, as discussed above, the language and the structure of the verdict sheet make clear that Questions 1 and 2 already asked whether a constitutional violation had occurred. Under the majority’s reading, Question 3 is essentially redundant. I believe the more logical reading is that Question 3 sought to resolve Saucier step two, i.e., the objective reasonableness of a mistake of law, whereas Questions 1 and 2 54 resolved Saucier step one, i.e., the objective reasonableness of a mistake of fact.29 As alluded to by the majority, my conclusion is in line with the understanding of the parties and the District Court. In its post-trial opinion, the District Court made clear that Question 3 asked the ultimate question of qualified immunity. The District Court stated that “the litigants agreed to submit the ultimate question of qualified immunity to the jury,”30 despite 29 That said, there is certainly some ambiguity in the verdict sheet, in large part because “objective reasonableness” is the standard by which a mistake of fact (or any decision based on real or perceived facts) and a mistake of law (or any decision based on a correct or incorrect understanding of the law) must be judged in the context of a Fourth Amendment case such as this one. See Maj. Slip Op. at 17-18 (noting that, in a Fourth Amendment case, Saucier steps one and two require an objective analysis of what is reasonable under the facts and the law, respectively). Courts create confusion by talking about “objective reasonableness” in the Fourth Amendment context without specific reference to either Saucier step one or two. 30 It should be noted, however, that Curley never agreed to submit the qualified immunity question to the jury. The record clearly reflects that Curley objected to the inclusion of Question 3 on the verdict sheet prior to its submission to the jury. Curley correctly noted that Question 3 asked about a purely “legal matter” that “should not be a jury question.” App. at T1062. 55 the fact that “there is Third Circuit law on the books that indicates the trial judge, and not the jury, decides qualified immunity.” Curley, 2006 WL 414093, at 1. Therefore, “the jury would decide the issue of qualified immunity,” id. at 4, “and in answering [Question 3] as they did, unanimously, this jury decided the issue of qualified immunity in Trooper Klem’s favor,” id. at 5. By interpreting Question 3 to apply to Saucier step one, rather than step two, the majority is rewriting history. Having concluded that Question 3 did, in fact, ask the ultimate question of qualified immunity, I consider whether it was permissible for the District Court to submit that question to the jury. I have no trouble concluding that it was not. Although the objective reasonableness of a mistake of fact is a question that the jury may answer, the jury may never consider the objective reasonableness of a mistake of law.31 See Carswell, 381 F.3d at 242 (“The court must make the ultimate determination on the availability of qualified immunity as a matter of law.”) (citing Curley I, 298 F.3d at 279 and Sharrar v. Felsing, 128 F.3d 810, 828 (3d Cir. 1997)). The majority agrees: “whether an officer made a reasonable mistake of law and is thus entitled to qualified immunity is a question of law that is properly answered by the court, not a jury.” Maj. Slip Op. at 25. This was the law at the time of trial, and this is the 31 In this case, the mistake of fact was for Klem to think that Curley was the fleeing perpetrator. The mistake of law, if there was one, would have been for Klem to think that the Fourth Amendment jurisprudence of the Supreme Court and this Court permitted the use of deadly force in this situation, when it did not. 56 law today. Although the jury may “determine[] disputed historical facts material to the qualified immunity question,” Carswell, 381 F.3d at 242, under no circumstances may the court delegate the ultimate question of qualified immunity to the jury, id., as was done in this case. Rather, the court should have decided – based on the facts of the case, as clarified by the special interrogatories – whether immunity was warranted under the Fourth Amendment jurisprudence of the Supreme Court and this Court. The majority suggests that our decision in Curley I left open the possibility of giving the ultimate question of qualified immunity to the jury. The majority points out that we stated in that case “that a jury can evaluate objective reasonableness when relevant factual issues are in dispute.” Maj. Slip Op. at 25 (quoting Curley I, 298 F.3d at 279). I disagree with the majority’s interpretation of Curley I. To the extent we were permitting juries to consider the question of “objective reasonableness,” we were referring to the objective reasonableness of one’s view of the facts (i.e., Saucier step one, which asks whether a violation occurred), as opposed to the objective reasonableness of one’s view of the law (i.e., Saucier step two, which asks whether a right was clearly established under the case law). See supra note 9. Indeed, we made clear the respective roles of the judge and jury in cases such as this one: “A jury must resolve these [fact] issues before a court can determine whether it would have been clear to a reasonable officer that Klem’s conduct was unlawful.” Curley I, 298 F.3d at 283. 57 The majority also suggests that our decisions in Sharrar and Karnes v. Skrutski, 62 F.3d 485 (3d Cir. 1995), both Fourth Amendment cases, demonstrate that “[w]e had previously permitted the jury to answer the key immunity question of whether the challenged behavior of a government official was objectively reasonable.” Maj. Slip Op. at 22. Although Sharrar and Karnes are not controlling in light of our subsequent cases, such as Carswell and Curley I, it is important to note that the majority’s suggestion concerning our supposedly “evolv[ing]” precedents, Maj. Slip Op. at 22, is not accurate and is the result of a misreading of Sharrar and Karnes that resembles the majority’s misreading of Curley I. In each instance, the majority improperly assumes that a jury empowered to address the objective reasonableness of one’s view of the facts may also address the objective reasonableness of one’s view of the law. That is not the case and never has been. We have never said that the qualified immunity question concerning the objective reasonableness of an officer’s view of the law may be submitted to the jury. “Objective reasonableness” can be a jury issue to the extent it applies to the question of whether, as a factual matter, a violation was committed. However, “objective reasonableness” is most definitely not a jury issue to the extent it applies to the question of whether, as a legal matter, a right was clearly established. Whether a right was clearly established is the “key immunity question”; we have never permitted a jury to answer that question. Indeed, we never would have said so because determining whether a right is clearly established – which requires a review of the applicable case law – is clearly outside the expertise of the jury. There is simply nothing in Sharrar or Karnes that permits submission of the ultimate 58 question of qualified immunity, i.e., Saucier step two, to the jury.32 32 For example, in Sharrar, we held “that in deciding whether defendant officers are entitled to qualified immunity it is not only the evidence of ‘clearly established law’ that is for the court but also whether the actions of the officers were objectively reasonable. Only if the historical facts material to the latter issue are in dispute . . . will there be an issue for the jury.” 128 F.3d at 828 (emphasis added). Therefore, we made clear that consideration of Saucier step two is exclusively reserved for the court. (Consequently, I believe the majority misstates the law by saying that, “in a line of cases beginning with Doe v. Groody, we began highlighting that ‘qualified immunity is an objective question to be decided by the court as a matter of law.’” Maj. Slip Op. at 23 (citation omitted). This basic proposition cited by the majority was well-established before Doe; it was previously set forth in Bartholomew v. Pennsylvania, 221 F.3d 425, 428 (3d Cir. 2000), where we actually cited Sharrar, 128 F.3d at 828 for support.) We went on to find no reversible error where the jury decided the objective reasonableness of what was essentially a mistake of fact, i.e., one officer’s mistaken belief that an accompanying officer had obtained a warrant. Id. at 830-31. In Karnes, we made the unremarkable statement that, “[w]hile the qualified immunity defense is frequently determined by courts as a matter of law, a jury should decide disputed factual issues relevant to that determination.” 62 F.3d at 491. We stopped short of saying that a jury may answer the ultimate question of qualified immunity, and we remanded for jury resolution of disputed 59 As previously noted, supra note 9, any ambiguity in our precedents exists because “objective reasonableness” is the standard by which mistake of facts and mistakes of law are to be judged in the context of the Fourth Amendment’s prohibition of unreasonable searches and seizures. Courts, including this one, create confusion by talking about “objective reasonableness” in the Fourth Amendment context without specific reference to either Saucier step one or two. The use of the term “objective reasonableness” without reference to factual or legal reasonableness is what has made this area of the law so confusing and it is why our precedents appear at times to say contradictory things with regard to the respective roles of judge and jury in determining objective reasonableness. I will try to clarify matters. If there are no disputed material facts, the court must determine the objective reasonableness of a mistake of fact (here, whether it was objectively reasonable for Klem to mistake Curley for the perpetrator). However, if there are triable issues of material fact, the jury must determine the objective reasonableness of that mistake of fact. With regard to the objective reasonableness of a mistake of law (here, whether it was objectively reasonable for Klem to believe that the law permitted him to use of deadly force against Curley in the situation at hand), the court should always determine this issue, because doing so requires a review of case law, which is not a task appropriate for the jury. (Of course, this second Saucier step need not be reached if it is established that no constitutional violation occurred. At that issues of credibility related to qualified immunity, but not qualified immunity itself. Id. at 499. 60 point, there is no violation, so there is no need for immunity analysis.) If there are no disputed material facts, the court should make this determination as soon as possible. However, if factual disputes relevant to this legal analysis do exist, the court will have to postpone making this determination until the jury resolves all the relevant factual disputes, because determining what actually happened is a prerequisite to determining whether the law clearly established that a particular action was permitted or prohibited by the Fourth Amendment under those circumstances. See Saucier, 533 U.S. at 202 (noting that step two asks “whether it would be clear to a reasonable officer that his conduct was unlawful in the situation he confronted”) (emphasis added). After the jury resolves these relevant fact disputes, presumably through the use of special interrogatories, see Curley I, 298 F.3d at 279 (suggesting this method), the court is then capable of deciding whether or not the law clearly permitted or prohibited the conduct constituting the constitutional violation. The District Court committed reversible error by submitting the ultimate question of qualified immunity to the jury by way of Question 3. Having so concluded, I next address what the District Court should have done instead. In doing so, I address what I believe to be the proper methods for handling qualified immunity where material fact disputes preclude resolution of that issue prior to trial. C. Proper Methods 61 After answering one of the two alternate liability questions in favor of Curley, the jury should have been instructed to proceed to Question 4, concerning proximate causation. The jury would have had to find that Klem’s shooting of Curley caused Curley’s injuries, since the evidence overwhelmingly reflected that fact and the issue was essentially uncontested. Indeed, at the charging conference, counsel for Klem agreed to place the proximate causation question separately at the bottom of the verdict sheet, rather than alongside each liability question, because causation was “not really a contested issue in this case.” App. at T1061-62. Next, the jurors should have been instructed to proceed to the separate damages verdict sheet, where they would have had to decide on dollar amounts that accurately reflected the economic and non- economic losses suffered by Curley as a result of Klem’s violation. After receiving the jury’s verdict for Curley, the District Court should have considered whether qualified immunity, Saucier step two, nevertheless prevented judgment from being entered against Klem. That would have been appropriate if the Fourth Amendment jurisprudence of the Supreme Court and this Court did not clearly establish that Klem’s conduct, in the circumstances at hand, was unlawful. In other words, if Klem’s conduct could have been the result of an objectively reasonable but mistaken view of law, he should have been entitled to qualified immunity. In making the ultimate qualified immunity determination for a Fourth Amendment case such as this one, the District Court should have reviewed the answers to the special 62 interrogatories in order to determine what actually happened. Then the District Court should have applied these findings to its survey of the relevant case law in order to determine if it was clearly established that a police officer was permitted to use deadly force in circumstances similar to the instant case. Post- trial briefing likely would have been helpful to the District Court in this regard. If the District Court had concluded that Klem was entitled to qualified immunity, judgment should have been entered for Klem, notwithstanding the jury’s verdict. If the District Court had made the opposite conclusion, judgment should have been entered for Curley. Either way, the District Court should have issued a written opinion explaining its reasoning with regard to qualified immunity. III. CONCLUSION In my view, the District Court improperly delegated the ultimate question of qualified immunity to the jury. I would vacate the judgment for Klem and remand the case so that the District Court can decide the question of qualified immunity in the first place.33 33 However, I would not remand to a different judge, as Curley requests, because there is little evidence, if any, of judicial bias. Curley attempts to show bias by pointing to several unremarkable rulings and remarks made by Judge Hayden during the official proceedings of this case. This Court has said, however, that such official judicial activity is almost never sufficient to warrant recusal under 28 U.S.C. § 455. See United States v. Bertoli, 40 F.3d 1384, 1412 (3d Cir. 1994) (citing Liteky v. United States, 510 U.S. 540, 554 63 The District Court considered post-trial motions regarding various issues, including potential inconsistencies in the verdict, and in doing so conducted some analysis of the special interrogatory answers. However, the District Court has not considered qualified immunity anew based on the jury’s answers to the special interrogatories and the relevant case law, which is what I believe the law in the Circuit requires. If the District Court were to conclude that Klem was not entitled to qualified immunity, a trial would have to be held on the damages issue, which never reached the jury. If, on the other hand, the court were to conclude that Klem was entitled to qualified immunity, then the court would have to set aside the liability verdict as it had before.34 (1994)). In addition, a new trial in not required, as Curley requests, for purported racial discrimination during juror selection. The District Court correctly concluded that Curley failed to make out a prima facie showing of racial discrimination during voir dire under Batson v. Kentucky, 476 U.S. 79, 96 (1986) and United States v. Milan, 304 F.3d 273, 281 (3d Cir. 2002). In any case, Klem’s race-neutral explanation for striking the juror at issue was adequate. 34 Although this Court might be able to conduct the immunity analysis for the first time on appeal based on a review of the law in light of the jury’s special interrogatory answers, the District Court is in a better position to do so. For example, the District Court, having sat through the trial and being very familiar with the facts, is in a better position to determine the meaning of answers to some of the more ambiguous special interrogatory questions (such as 64 Although the outcome reached by the majority brings closure to nine years of litigation in this difficult case, I do not believe that this outcome is the correct one. In my view, the majority’s decision is not faithful to its own opinion, Curley I, or our other precedents, and thus should be modified as I have proposed. Interrogatory 7, see supra note 2), and to consider how they apply to the Saucier step two analysis. That said, it would be surprising if the District Court were to grant qualified immunity in this situation given Klem’s admission in his appellate brief that the issue in this case “is not whether there was a misunderstanding of the law.” Klem Br. at 25; see also Klem Br. at 2 (“This case, involving a ‘friendly fire’ shooting as a result of mistaken identity, is one of the class of Fourth Amendment and qualified immunity cases where the decisive issue is whether a police officer has made a reasonable mistake of fact in carrying out his duties.”) (emphasis added). 65	{ "pile_set_name": "FreeLaw" }
Infected Mushroom has been one of the most highly recognized names in electronic music over the years, with their most recent drop off Dim Mak last month titled Army of Mushrooms . Schoolboy, who has gained my attention through his unbelievably massive remix of Antidote, is at it again taking this laidback electro house record to a whole new level. We can expect the official drop of the remix off Dim Mak in the near future, but for now I highly suggest grabbing his remix of Antidote below:	{ "pile_set_name": "Pile-CC" }
package com.lzx.lock.utils; import java.security.MessageDigest; import java.security.NoSuchAlgorithmException; /** * Created by xian on 2017/2/17. / public class StringUtil { public static String toMD5(String source) { if (null == source \|\| "".equals(source)) return null; try { MessageDigest digest = MessageDigest.getInstance("MD5"); digest.update(source.getBytes()); return toHex(digest.digest()); } catch (NoSuchAlgorithmException e) { } return null; } public static String toHex(byte[] buf) { if (buf == null) return ""; StringBuffer result = new StringBuffer(2 buf.length); for (int i = 0; i < buf.length; i++) { appendHex(result, buf[i]); } return result.toString(); } private final static String HEX = "0123456789ABCDEF"; private static void appendHex(StringBuffer sb, byte b) { sb.append(HEX.charAt((b >> 4) & 0x0f)).append(HEX.charAt(b & 0x0f)); } }	{ "pile_set_name": "Github" }
Agnus Agnus (Latin for lamb) can be used to refer to : People with the surname Felix Agnus (1839-1925), American military officer and newspaper publisher Religion Agnus Dei (Latin: "Lamb of God") referring to Jesus Christ as divine sacrificial lamb an early prayer of the breviary Places and jurisdictions Agnus (Egypt), an Ancient city and former bishopric in Aegyptus Primus, now a Latin Catholic titular see Agnus (Attica), a deme of ancient Attica Biology Agnus scythicus, Latin for Vegetable Lamb of Tartary, a mythologic lamb-plant Agnus (beetle), a stag beetle genus Technology MOS Technology Agnus, an integrated circuit in the OCS chipset of the Commodore Amiga computer	{ "pile_set_name": "Wikipedia (en)" }